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Potential use of bacterial pigments as anticancer drugs and female reproductive toxicity: a review

Abstract

Natural bioactive compounds obtained from microorganisms, have awakened particular interest in the industry nowadays. This attention comes when natural resources depletion is pronounced, and the acquisition of both new plant origin resources and bioactive products, represents a challenge for the next generations. In this sense, prospecting for large-scale production and use of bacterial pigments is a necessary strategy for the development of novel products. A wide variety of properties have been attributed to these substances and, among them, their therapeutic potential against important diseases, such as cancer. There is consensus that available chemotherapy protocols are known to detrimentally affect cancer patients fertility. Hence, considerable part of the deleterious effects of chemotherapy is related to the drugs cytotoxicity, which, in addition to cancer cells, also affect normal cells. Therefore, the intrinsic properties of bacterial pigments associated with low cytotoxicity and relevant cell selectivity, certified them as potential anticancer drugs. However, little information is available about reproductive toxicity of these new and promising compounds. Thus, the present review aims to address the main bacterial pigments, their potential uses as anticancer drugs and their possible toxic effects, especially on the female gonad.

Keywords:
cancer; chemotherapy; fertility; bioactive compounds; bacteria

Resumo

Os compostos bioativos naturais obtidos de microrganismos têm despertado especial interesse da indústria nos últimos anos. Esta atenção ocorre em um momento em que o esgotamento de recursos naturais é pronunciado, e a aquisição de novos insumos e produtos bioativos de origem vegetal representa um desafio para as próximas gerações. Neste sentido, a prospecção para a produção e uso em larga escala dos pigmentos bacterianos tem representado uma importante estratégia para o desenvolvimento de novos produtos. Uma grande variedade de propriedades foi atribuída a estas substâncias, entre elas, o potencial terapêutico contra doenças importantes, como o câncer. Existe um consenso de que os protocolos quimioterápicos disponíveis são conhecidos por afetarem negativamente a fertilidade de pacientes com câncer. Grande parte dos efeitos deletérios da quimioterapia está relacionado à citotoxicidade das drogas usadas para este fim, que além das células cancerosas, afetam as células normais. Nesse sentido, as propriedades naturais atribuídas aos pigmentos bacterianos associadas à baixa citotoxicidade e relevante seletividade, os qualificaram como potenciais drogas anticâncer. No entanto, pouco se tem de informação a respeito da toxicidade reprodutiva destes novos e promissores compostos. Dessa forma, a presente revisão tem o objetivo de abordar os principais pigmentos bacterianos, suas utilizações potenciais como drogas anticâncer, bem como os seus possíveis efeitos tóxicos, sobretudo, sobre a gônada feminina.

Palavras-chave:
câncer; quimioterapia; fertilidade; compostos bioativos; bactéria

Introduction

The mammalian ovary, as well as any organs that compound an organism, are continuously subject to several cytotoxic factors that may affect, and modify, its biological functions. One of the main consequences of the ovaries continuous exposure to cytotoxic agents is premature ovarian failure [POF(11 Pope CN, Schlenk D, Baud FJ. History and basic concepts of toxicology. In: An Introduction to Interdisciplinary Toxicology. Elsevier; 2020. p. 3-15. doi: 10.1016/B978-0-12-813602-7.00001-6
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,22 Zhang T, Yan D, Yang Y, Ma A, Li L, Wang Z, et al. The comparison of animal models for premature ovarian failure established by several different source of inducers. Regul Toxicol Pharmacol. 2016;81:223-32. doi: 10.1016/j.yrtph.2016.09.002
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)]. POF may be the direct consequence and the main side effect of chemotherapy drugs currently used for the cancer treatment(33 Nieman CL, Kazer R, Brannigan RE, Zoloth LS, Chase-Landsdale PL, Kinahan K, et al. Cancer survivors and infertility: A review of a new problem and novel answers. J Support Oncol. 2006;4(4):171-8. https://www.researchgate.net/publication/7112088
https://www.researchgate.net/publication...
).

Ovarian damage, with consequent permanent infertility, is one of the most common side effects during chemotherapy treatment in women with certain types of cancer, such as Hodgkin's lymphoma(44 Familiari G, Caggiati A, Nottola SA, Ermini M, Benedetto MR Di, Motta PM. Infertility: Ultrastructure of human ovarian primordial follicles after combination chemotherapy for hodgkin’s disease. Hum Reprod. 1993;8(12):2080-7. doi: 10.1093/oxfordjournals.humrep.a137985
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). In order to mitigate chemotherapy harmful effects on female fertility, studies have investigated the influence of several anticancer potential substances, including natural bioactive compounds with low cytotoxicity and chemoprotective action, such as resveratrol(55 Jang M, Cai L, Udeani GO, Slowing K V., Thomas CF, Beecher CWW, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275(5297):218-20. doi: 10.1126/science.275.5297.218
https://doi.org/10.1126/science.275.5297...
); lycopene(66 Mohanty NK, Saxena S, Singh UP, Goyal NK, Arora RP. Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol Semin Orig Investig. 2005;23(6):383-5. doi: 10.1016/j.urolonc.2005.05.012
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7 Liu X, Lin X, Zhang S, Guo C, Li J, Mi Y, et al. Lycopene ameliorates oxidative stress in the aging chicken ovary via activation of Nrf2/HO-1 pathway. Aging. 2018;10(8):2016-36. doi: 10.18632/aging.101526
https://doi.org/10.18632/aging.101526...

8 Residiwati G, Azari-Dolatabad N, Tuska HSA, Sidi S, Van Damme P, Benedetti C, et al. Effect of lycopene supplementation to bovine oocytes exposed to heat shock during in vitro maturation. Theriogenology. 2021;173:48-55. doi: 10.1016/j.theriogenology.2021.07.014
https://doi.org/10.1016/j.theriogenology...
-99 Sidi S, Pascottini OB, Angel-Velez D, Azari-Dolatabad N, Pavani KC, Residiwati G, et al. Lycopene supplementation to serum-free maturation medium improves in vitro bovine embryo development and quality and modulates embryonic transcriptomic Profile. Antioxidants. 2022;344(11):3-18. doi: 10.3390/antiox11020344
https://doi.org/10.3390/antiox11020344...
); fennel extract(1010 Hassanpour A, Yousefian S, Askaripour M, Sharififar F, Ezzatabadipour M. Ovarian protection in cyclophosphamide-treated mice by fennel. Toxicol Reports [Internet]. 2017;4:160-4. Available from: https://doi.org/10.1016/j.toxrep.2017.03.002
https://doi.org/10.1016/j.toxrep.2017.03...
) and melatonin(1111 Moselhy SS, Al Mslmani MAB. Chemopreventive effect of lycopene alone or with melatonin against the genesis of oxidative stress and mammary tumors induced by 7,12 dimethyl(a)benzanthracene in sprague dawely female rats. Mol Cell Biochem. 2008;319(1-2):175-80. doi: 10.1007/s11010-008-9890-6
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,1212 Palomino GJQ, Sá NAR, Guerreiro DD, Gomes FDR, Silva RF, Lopes EPF, et al. Induced-damages on preantral follicles by withanolide D, a potent chemotherapy candidate are not attenuated by melatonin. Reprod Toxicol. 2021;104:125-33. doi: 10.1016/j.reprotox.2021.07.005
https://doi.org/10.1016/j.reprotox.2021....
).

Natural bioactive compounds can be extracted from plant or animal sources(1313 Fernandes SS, Coelho MS, Salas-Mellado M de las M. Bioactive compounds as ingredients of functional foods: polyphenols, carotenoids, peptides from animal and plant sources new [Internet]. Bioactive Compounds: Health Benefits and Potential Applications. Elsevier Inc.; 2018. 129-142 p. Available from: https://doi.org/10.1016/B978-0-12-814774-0.00007-4
https://doi.org/10.1016/B978-0-12-814774...
). However, some microorganisms represent the most important and promising sources of these compounds(1414 Ran X, Zhang G, Li S, Wang J. Characterization and antitumor activity of camptothecin from endophytic fungus Fusarium solani isolated from Camptotheca acuminate. Afr Health Sci. 2017;17(2):566-74. doi: 10.4314/ahs.v17i2.34
https://doi.org/10.4314/ahs.v17i2.34...
,1515 Anwar MM, Shalaby M, Embaby AM, Saeed H, Agwa MM, Hussein A. Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights. Sci Rep [Internet]. 2020;10(1):1-15. Available from: https://doi.org/10.1038/s41598-020-71157-w
https://doi.org/10.1038/s41598-020-71157...
). Natural bioactive compounds are characterized by their variety of therapeutic properties, which can be explored as alternative to the use of highly cytotoxic chemotherapeutics, or as adjuvant drugs in the chemotherapy. Microorganisms (fungi and bacteria) are rich sources of bioactive compounds with anticancer effects(1313 Fernandes SS, Coelho MS, Salas-Mellado M de las M. Bioactive compounds as ingredients of functional foods: polyphenols, carotenoids, peptides from animal and plant sources new [Internet]. Bioactive Compounds: Health Benefits and Potential Applications. Elsevier Inc.; 2018. 129-142 p. Available from: https://doi.org/10.1016/B978-0-12-814774-0.00007-4
https://doi.org/10.1016/B978-0-12-814774...

14 Ran X, Zhang G, Li S, Wang J. Characterization and antitumor activity of camptothecin from endophytic fungus Fusarium solani isolated from Camptotheca acuminate. Afr Health Sci. 2017;17(2):566-74. doi: 10.4314/ahs.v17i2.34
https://doi.org/10.4314/ahs.v17i2.34...
-1515 Anwar MM, Shalaby M, Embaby AM, Saeed H, Agwa MM, Hussein A. Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights. Sci Rep [Internet]. 2020;10(1):1-15. Available from: https://doi.org/10.1038/s41598-020-71157-w
https://doi.org/10.1038/s41598-020-71157...
), being excellent pigments producers [pyocyanin(1616 Kerr JR, Taylor GW, Rutman A, Høiby N, Cole PJ, Wilson R. Pseudomonas aeruginosa pyocyanin and 1-hydroxyphenazine inhibit fungal growth. J Clin Pathol. 1999;52(5):385-7. doi: 10.1136/jcp.52.5.385
https://doi.org/10.1136/jcp.52.5.385...
,1717 Marrez DA, Mohamad HS. Biological activity and applications of pyocyanin produced by Pseudomonas aeruginosa. Open Access J Biomed Sci. 2020;1(4):140-4. doi: 10.38125/OAJBS.000133
https://doi.org/10.38125/OAJBS.000133...
); prodigiosin(1818 Borić M, Danevčič T, Stopar D. Prodigiosin from Vibrio sp. DSM 14379; A New UV-Protective Pigment. Microb Ecol. 2011;62(3):528-36. doi: 10.1007/s00248-011-9857-0
https://doi.org/10.1007/s00248-011-9857-...
,1919 Guryanov I, Naumenko E, Akhatova F, Lazzara G, Cavallaro G, Nigamatzyanova L, et al. Selective cytotoxic activity of prodigiosin@halloysite nanoformulation. Front Bioeng Biotechnol. 2020;8:1-13. doi: 10.3389/fbioe.2020.00424
https://doi.org/10.3389/fbioe.2020.00424...
); carotenoids(2020 Reis-Mansur MCPP, Cardoso-Rurr JS, Silva JVMA, Souza GR, Cardoso VS, Mansoldo FRP, et al. Carotenoids from UV-resistant Antarctic Microbacterium sp. LEMMJ01. Sci Rep. 2019;9(9554):1-14. doi: 10.1038/s41598-019-45840-6
https://doi.org/10.1038/s41598-019-45840...
,2121 Ram S, Mitra M, Shah F, Tirkey SR, Mishra S. Bacteria as an alternate biofactory for carotenoid production: A review of its applications, opportunities and challenges. J Funct Foods [Internet]. 2020;67:103867. Available from: https://doi.org/10.1016/j.jff.2020.103867
https://doi.org/10.1016/j.jff.2020.10386...
)]. Pigments generated by microorganisms, especially bacteria, can contribute to the development of new therapeutic approaches for cancer treatment and/or in the preservation of female fertility. Thus, this work aims to address the main bacterial pigments, their potential uses as anticancer drugs as well as their possible toxic effects on the female reproductive system.

Chemotherapeutic agents and their anticancer mechanisms

Chemotherapeutic agents are drugs commonly used in therapeutic protocols for the treatment of the most varied cancer types. They are generally semi-synthetic or synthetic substances of different origins, such as plants and microorganisms(2222 Malhotra V, Perry MC. Classical chemotherapy: mechanisms, toxicities and the therapeutic window. Cancer Biol Ther. 2003;2(4):1-4. https://doi.org/10.4161/cbt.199
https://doi.org/10.4161/cbt.199...
). In fact, there are four classes of plant-derived anticancer agents, namely: vinca alkaloids (vincristine, vinblastine, and vindesine), epipodophyllotoxins (etoposide and teniposide), taxanes (paclitaxel and docetaxel) and camptothecin derivatives [camptothecin and irinotecan(2323 Desai A, Qazi G, Ganju R, El-Tamer M, Singh J, Saxena A, et al. Medicinal plants and cancer chemoprevention. Curr Drug Metab. 2008;9(7):581-91. doi: 10.2174/138920008785821657
https://doi.org/10.2174/1389200087858216...
)]. Other chemotherapeutic agents derived from anthracyclines and produced by microorganisms, such as doxorubicin (DOX), are highly effective in the treatment of different types of tumors(2424 Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014;74(1):104-18. doi: 10.1158/0008-5472.CAN-13-1545
https://doi.org/10.1158/0008-5472.CAN-13...
). These drugs, however, show high degree of toxicity to non-cancerous cells. This occurs because chemotherapeutic action mechanisms are not selective, causing normal cells depletion, especially those with a high degree of proliferative activity(2525 Borenfreund E, Babich H, Martin-alguacil A. Rapid chemosensitivity assay with human normal and tumor cells in vitro. Vitr Cell Dev Biol. 1990;26(11):1030-4. doi: 10.1007/BF02624436
https://doi.org/10.1007/BF02624436...
,2626 Zhao R, Liu X, Yang X, Jin B, Shao C, Kang W, et al. Nanomaterial-based organelles protect normal cells against chemotherapy-induced cytotoxicity. Adv Mater. 2018;30(27):1-8. doi: 10.1002/adma.201801304
https://doi.org/10.1002/adma.201801304...
).

Specifically concerning the reproductive tract, drugs such as DOX cause apoptosis-induced damage to the primordial follicle pool, inducing double-strand breaks in DNA and causing stromal cell death, as well as microvascular damage that induces tissue hypoxia, contributing to the early loss of ovarian follicles(2727 Titus S, Szymanska KJ, Musul B, Turan V, Taylan E, Garcia- Milian R, et al. Individual-oocyte transcriptomic analysis shows that genotoxic chemotherapy depletes human primordial follicle reserve in vivo by triggering proapoptotic pathways without growth activation. Sci Rep. 2021;11(407):1-10. doi: 10.1038/s41598-020-79643-x
https://doi.org/10.1038/s41598-020-79643...
). Other chemotherapeutic drugs, such as cyclophosphamide, are metabolized in the liver and transformed into active alkylating metabolites(1010 Hassanpour A, Yousefian S, Askaripour M, Sharififar F, Ezzatabadipour M. Ovarian protection in cyclophosphamide-treated mice by fennel. Toxicol Reports [Internet]. 2017;4:160-4. Available from: https://doi.org/10.1016/j.toxrep.2017.03.002
https://doi.org/10.1016/j.toxrep.2017.03...
). These metabolites induce the activation of DNA-PK - γH2AX- checkpoint kinase 2 (CHK2), p53/TAp63α, protein kinase B (AKT), and forkhead box O3 (FOXO3a) isoforms in the oocyte nucleus. Such proteins are involved in DNA damage and repair, and in processes like apoptosis and cellular autophagy (2828 Bellusci G, Mattiello L, Iannizzotto V, Ciccone S, Maiani E, Villani V, et al. Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility. Cell Death Dis. 2019;10(10):1-14. doi: 10.1038/s41419-019-1961-y
https://doi.org/10.1038/s41419-019-1961-...
). Table 1 presents the main mechanisms and the gonadotoxicity of the important chemotherapeutic agents.

Table 1
Main classes of chemotherapeutics and their anticancer and gonadotoxic mechanisms

Cytotoxicity of chemotherapeutic agents on the female reproductive system

Among the structures that conform the female reproductive system, the ovarian follicles and their respective oocytes are highly sensitive to the chemotherapy deleterious effects, which speeds up follicular atresia promoting the ovarian reserve depletion(3434 Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, et al. Cyclophosphamide triggers follicle activation and "burnout "; AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5(185):1-9. doi: 10.1126/scitranslmed.3005402
https://doi.org/10.1126/scitranslmed.300...
). The gonadotoxic effect of chemotherapeutics can occur because of three known factors: 1- due to failures in DNA damage and repair mechanisms. These failures result in the Tap 73 protein activation, a p53 modulator that is upregulated in apoptosis, which also activates the pro-apoptotic protein p63. Tap 73 and p53 recruit and activate the pro-apoptotic proteins Bax and Bak, inducing apoptosis(3333 Kim S, Lee S, Park HT, Song JY, Kim T. Genomic consideration in chemotherapy-induced ovarian damage and fertility preservation. Genes. 2021;12(10):1525. doi: /10.3390/ genes12101525
https://doi.org//10.3390/genes12101525...
); 2- Burnout effect; process that induces depletion of follicular reserve due to reducing the secretion of anti-Mullerian hormone (AMH), substance that inhibits primordial follicles activation and recruitment(3434 Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, et al. Cyclophosphamide triggers follicle activation and "burnout "; AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5(185):1-9. doi: 10.1126/scitranslmed.3005402
https://doi.org/10.1126/scitranslmed.300...
,3535 Yang M, Cushman RA, Fortune JE. Anti-Mullerian hormone inhibits activation and growth of bovine ovarian follicles in vitro and is localized to growing follicles. Mol Hum Reprod. 2017;23(5):282-91. doi: 10.1093/molehr/gax010
https://doi.org/10.1093/molehr/gax010...
). The reduced levels of AMH in the bloodstream culminate in amplifying follicular activation and depletion(3636 Sonigo C, Beau I, Binart N, Grynberg M. The impact of chemotherapy on the ovaries: Molecular aspects and the prevention of ovarian damage. Int J Mol Sci. 2019;20(21):5342. doi: 10.3390/ijms20215342
https://doi.org/10.3390/ijms20215342...
), and 3- related to vascular damage promotion. Studies indicated that chemotherapeutic agents such as DOX induce vascular damage(3737 Bar-Joseph H, Ben-Aharon I, Tzabari M, Tsarfaty G, Stemmer SM, Shalgi R. In vivo bioimaging as a novel strategy to detect Doxorubicin-Induced damage to gonadal blood vessels. PLoS One. 2011;6(9):1-8. doi: 10.1371/journal.pone.0023492
https://doi.org/10.1371/journal.pone.002...
). This is reflected by a drop in ovarian arterial flow, inducing hypoxia and ovarian atrophy accompanied by cortical fibrosis, follicular loss, and a significant reduction in ovarian and, consequently, reproductive function(3838 Meirow D, Dor J, Kaufman B, Shrim A, Rabinovici J, Schiff E, et al. Cortical fibrosis and blood-vessels damage in human ovaries exposed to chemotherapy. Potential mechanisms of ovarian injury. Hum Reprod. 2007;22(6):1626-33. doi: 10.1093/humrep/dem027
https://doi.org/10.1093/humrep/dem027...
). The early reduction of ovarian function due to the use of chemotherapeutic drugs to treat cancer can characterize POF in cancer patients.

POF and the use of animals as a model for the study of reproductive disorders

POF affects approximately 1% of women under 40 years of age, being the primary cause of reproductive disorders, such as anovulation and hypoestrogenism, primary or secondary amenorrhea, infertility, sex steroid deficiency and blood elevation levels of gonadotropin(3939 Goswami D, Conway GS. Premature ovarian failure. Human Reproduction Update. 2005;11(4):391-410. doi: 10.1093/humupd/dmi012
https://doi.org/10.1093/humupd/dmi012...
). POF onset is usually idiopathic(4040 Ghahremani-Nasab M, Ghanbari E, Jahanbani Y, Mehdizadeh A, Yousefi M. Premature ovarian failure and tissue engineering. J Cell Physiol. 2020;235(5):4217-26. doi: 10.1002/jcp.29376
https://doi.org/10.1002/jcp.29376...
). However, several non-physiological mechanisms may be associated with its development, which may include genetic, autosomal, autoimmune, metabolic and infectious diseases(4141 Ebrahimi M, Asbagh FA. Pathogenesis and causes of premature ovarian failure: An update. Int J Fertil Steril. 2011;5(2):54-65.). Anticancer treatments based on chemotherapy and radiotherapy, for example, are the best-known iatrogenic causes for the establishment and development of this disorder(4141 Ebrahimi M, Asbagh FA. Pathogenesis and causes of premature ovarian failure: An update. Int J Fertil Steril. 2011;5(2):54-65.).

Also, POF is a human condition that has not been reported in animals. However, domestic animals, and especially ruminants, share important similarities with the human species in terms of reproductive aspects, such as duration of the ovulatory cycle (female: 24-30 days, cow: 17-24 days, sheep: 13-19 days), number of ovulations per cycle (female: 1, cow: 1, sheep: 1-2), duration of luteal phase (female: 14-16 days, cow: 15-18 days, sheep: 12-14 days), ovulatory follicle diameter (female: 18-20 mm, cow: 15-20 mm) and duration of gestation [female: ~9 months, cow: ~9 months(4242 Abedal-Majed MA, Cupp AS. Livestock animals to study infertility in women. Anim Front. 2019;9(3):28-33. doi: 10.1093/af/vfz017
https://doi.org/10.1093/af/vfz017...
)]. In addition, non-humans reproductive system may be equally susceptible to disorders that directly or indirectly promote reproductive dysfunction. Thus, due to the similarities they share with the human species in terms of reproductive aspects, some domestic animals can serve as experimental models for studies of fertility and female reproductive toxicology(22 Zhang T, Yan D, Yang Y, Ma A, Li L, Wang Z, et al. The comparison of animal models for premature ovarian failure established by several different source of inducers. Regul Toxicol Pharmacol. 2016;81:223-32. doi: 10.1016/j.yrtph.2016.09.002
https://doi.org/10.1016/j.yrtph.2016.09....
,4242 Abedal-Majed MA, Cupp AS. Livestock animals to study infertility in women. Anim Front. 2019;9(3):28-33. doi: 10.1093/af/vfz017
https://doi.org/10.1093/af/vfz017...
,4343 Bandyopadhyay S, Chakrabarti J, Banerjee S, Pal AK, Goswami SK, Chakravarty BN, et al. Galactose toxicity in the rat as a model for premature ovarian failure: An experimental approach readdressed. Hum Reprod. 2003;18(10):2031-8. doi: 10.1093/humrep/deg414.
https://doi.org/10.1093/humrep/deg414....
).

Bacterial pigments importance

Because of the cyto/gonadotoxicity of chemotherapeutics drugs, several studies have investigated the use of new therapies, based on new substances discovery to prevent, treat, and control several types of cancer. These studies seek substances that show a higher selectivity index for cancer cells or that can be used as adjuvants in the chemotherapy, attenuating the toxic effects of chemotherapeutics and helping to preserve healthy tissues(1515 Anwar MM, Shalaby M, Embaby AM, Saeed H, Agwa MM, Hussein A. Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights. Sci Rep [Internet]. 2020;10(1):1-15. Available from: https://doi.org/10.1038/s41598-020-71157-w
https://doi.org/10.1038/s41598-020-71157...
,4444 Bromberg N, Dreyfuss JL, Regatieri C V., Palladino M V., Durán N, Nader HB, et al. Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor. Chem Biol Interact. 2010;186(1):43-52. doi: 10.1016/j.cbi.2010.04.016
https://doi.org/10.1016/j.cbi.2010.04.01...

45 Kodach LL, Bos CL, Durán N, Peppelenbosch MP, Ferreira C V., Hardwick JCH. Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells. Carcinogenesis. 2006;27(3):508-16. doi: 10.1093/carcin/bgi307
https://doi.org/10.1093/carcin/bgi307...
-4646 El-Naggar N, El-Ewasy SM. Bioproduction, characterization, anticancer and antioxidant activities of extracellular melanin pigment produced by newly isolated microbial cell factories Streptomyces glauscescens NEAE-H. Sci Rep. 2017;7:1-19. doi: 10.1038/srep42129
https://doi.org/10.1038/srep42129...
). In this sense, bacterial strains have ability to naturally produce an infinity of metabolites. Some metabolites produced by bacteria are classified as pigments because present some type of coloration in visible light spectrum(4747 Arun G, Eyini M, Gunasekaran P. Characterization and biological activities of extracellular melanin produced by Schizophyllum commune (Fries). Indian J Exp Biol. 2015;53(6):380-7.). These substances showed a variety of functions and properties that, generally, act as virulence factors (determining the pathogenicity of different bacterial strains), providing thermal and light resistance against ultraviolet radiation, and promoting redox balance [preventing against oxidative stress(4848 Pavan ME, López NI, Pettinari MJ. Melanin biosynthesis in bacteria, regulation and production perspectives. Appl Microbiol Biotechnol. 2020;104(4):1357-70. doi: 10.1007/s00253-019-10245-y
https://doi.org/10.1007/s00253-019-10245...
)].

Bacterial pigments have awakened the industry interest on several fronts: in human food sector, as dyes and natural antioxidant additives(4949 Darshan N, Manonmani HK. Prodigiosin and its potential applications. J Food Sci Technol. 2015;52(9):5393-407. doi: 10.1007/s13197-015-1740-4
https://doi.org/10.1007/s13197-015-1740-...
); in the production of new generations of antibiotics and antifungals, due to the multiple resistance of microorganisms to substances routinely prescribed by the medical community(5050 Azman AS, Mawang CI, Abubakar S. Bacterial pigments: The bioactivities and as an alternative for therapeutic applications. Nat Prod Commun. 2018;13(12):1747-54. doi: 10.1177/1934578X1801301240
https://doi.org/10.1177/1934578X18013012...
); in the cosmetic industry, aiming to create new photoprotective and antioxidant formulations(5151 Suryawanshi RK, Patil CD, Borase HP, Narkhede CP, Stevenson A, Hallsworth JE, et al. Towards an understanding of bacterial metabolites prodigiosin and violacein and their potential for use in commercial sunscreens. Int J Cosmet Sci. 2015;37(1):98-107. doi: 10.1111/ics.12175
https://doi.org/10.1111/ics.12175...
); in the animal food formulation and supplementation, with the purpose of increase animal performance and development(5252 Meza-Herrera CA, Vargas-Beltran F, Tena-Sempere M, González-Bulnes A, Macias-Cruz U, Veliz-Deras FG. Short-term betacarotene supplementation positively affects ovarian activity and serum insulin concentrations in a goat model. J Endocrinol Invest. 2013;36(3):185-9. doi: 10.3275/8410
https://doi.org/10.3275/8410...

53 Meza-Herrera CA, Reyes-Avila JM, Tena-Sempere M, Veliz-Deras FG, Macias-Cruz U, Rodriguez-Martinez R, et al. Long-term betacarotene supplementation positively affects serum triiodothyronine concentrations around puberty onset in female goats. Small Rumin Res [Internet]. 2014;116(2):176-82. Available from: http://dx.doi.org/10.1016/j.smallrumres.2013.10.017
http://dx.doi.org/10.1016/j.smallrumres....
-5454 Venil CK, Dufossé L, Renuka Devi P. Bacterial Pigments: Sustainable Compounds With Market Potential for Pharma and Food Industry. Front Sustain Food Syst. 2020;4:1-17. doi: 10.3389/fsufs.2020.00100
https://doi.org/10.3389/fsufs.2020.00100...
); and in the treatment of cancer, owing to its effectiveness against different cancer cells lines in animals and humans. Figure 1 illustrates the main and potential applications of bacterial pigments.

The use of bacterial pigments in biotechnology and pharmacology is trending worldwide. Pigments are highly bioactive compounds that exhibit many properties of social and economic interest. In addition, bacterial pigments production and acquisition represent several benefits that justify such interest, as well as the possibility of large-scale production, since the incubation of bacteria is relatively simple and stimulate the development of millions and millions of colonies(4949 Darshan N, Manonmani HK. Prodigiosin and its potential applications. J Food Sci Technol. 2015;52(9):5393-407. doi: 10.1007/s13197-015-1740-4
https://doi.org/10.1007/s13197-015-1740-...
). Additionally, mastering the genetic manipulation of microorganisms allowed continuous improvement of bacterial origin pigments production, thanks to transgenesis and gene editing. In this sense, chemotherapeutic agents of plant origin, such as the vinca alkaloids - vincristine and vinblastine - extracted from Catharanthus roseus, and taxane - paclitaxel - for example, were successful synthesized by yeasts(5555 Courdavault V, O’Connor SE, Oudin A, Besseau S, Papon N. Towards the Microbial Production of Plant-Derived Anticancer Drugs. Trends in Cancer [Internet]. 2020;6(6):444-8. Available from: https://doi.org/10.1016/j.trecan.2020.02.004
https://doi.org/10.1016/j.trecan.2020.02...
), and biosynthesized by a variety of bacteria(5656 Flores-Bustamante ZR, Rivera-0rdũa FN, Martínez-Cárdenas A, Flores-Costera LB. Microbial paclitaxel: Advances and perspectives. J Antiot. 2010;63(8):460-7. doi: 10.1038/ja.2010.83
https://doi.org/10.1038/ja.2010.83...
), respectively. Furthermore, thanks to recombinant DNA technology, non-violacein-producing Escherichia coli bacteria modified with plasmids, which expressed synthetic vioABCDE operons - involved in pigment synthesis - successfully produced this pigment, which has vast pharmacological potential(5757 Bilsland E, Tavella TA, Krogh R, Stokes JE, Roberts A, Ajioka J, et al. Antiplasmodial and trypanocidal activity of violacein and deoxyviolacein produced from synthetic operons. BMC Biotechnol. 2018;18(1):1-8. doi: 10.1186/s12896-018-0428-z
https://doi.org/10.1186/s12896-018-0428-...
).

Furthermore, pigments production derived from bacteria with diverse pharmacological potential, including anticancer, has a positive impact for environment, since bacterial cultivation eliminates the need to plant extensive areas of monocultures traditionally used to obtain vegetable origin chemotherapeutic drugs(5555 Courdavault V, O’Connor SE, Oudin A, Besseau S, Papon N. Towards the Microbial Production of Plant-Derived Anticancer Drugs. Trends in Cancer [Internet]. 2020;6(6):444-8. Available from: https://doi.org/10.1016/j.trecan.2020.02.004
https://doi.org/10.1016/j.trecan.2020.02...
). Therefore, reducing fertilizers and pesticides use, which are known to affect negatively human health and female fertility(5858 Aloo BN, Makumba BA, Mbega ER. The potential of Bacilli rhizobacteria for sustainable crop production and environmental sustainability. Microbiol Res [Internet]. 2019;219:1-33. Available from: https://doi.org/10.1016/j.micres.2018.10.011
https://doi.org/10.1016/j.micres.2018.10...
). For these reasons, bacterial pigments production and use represent a window for promising advances in the coming decades. Hereafter, the main bacterial pigments with anticancer potential currently known will be discussed.

Figure 1
Potential applications for commercial use of bacterial pigments.

Carotenoids

Carotenoids are a wide variety of natural biomolecules produced by plants, algae, yeast, fungi and bacteria. They have different colours from red, yellow to orange, and belong to the isoprenoid subfamily(2121 Ram S, Mitra M, Shah F, Tirkey SR, Mishra S. Bacteria as an alternate biofactory for carotenoid production: A review of its applications, opportunities and challenges. J Funct Foods [Internet]. 2020;67:103867. Available from: https://doi.org/10.1016/j.jff.2020.103867
https://doi.org/10.1016/j.jff.2020.10386...
). These pigments are classified into two main groups: pure hydrocarbons, carotenes (α-carotene, β-carotene and lycopene), and oxygenated derivatives, xanthophylls [lutein, zeaxanthin, astaxanthin(5959 Aryee AN, Agyei D, Akanbi TO. Recovery and utilization of seaweed pigments in food processing. Curr Opin Food Sci [Internet]. 2018;19:113-9. Available from: https://doi.org/10.1016/j.cofs.2018.03.013
https://doi.org/10.1016/j.cofs.2018.03.0...
)]. In bacteria, carotenoids are secondary metabolites that play fundamental roles for cellular adaptability, protecting from ultraviolet radiation and oxidative damage, as well as acting in the mechanisms of maintenance of cell membrane fluidity(6060 Vila E, Hornero-Méndez D, Azziz G, Lareo C. Carotenoids from heterotrophic bacteria isolated from Fildes Peninsula, King George Island, Antarctica. Biotechnol Reports. 2018;20:1-7. doi: 10.1016/j.bre.2019.e00306
https://doi.org/10.1016/j.bre.2019.e0030...
). Several bacteria genres have been reported to produce carotenoid pigments, such as astaxanthin, β-carotene, zeaxanthin, canthaxanthin and lycopene(2121 Ram S, Mitra M, Shah F, Tirkey SR, Mishra S. Bacteria as an alternate biofactory for carotenoid production: A review of its applications, opportunities and challenges. J Funct Foods [Internet]. 2020;67:103867. Available from: https://doi.org/10.1016/j.jff.2020.103867
https://doi.org/10.1016/j.jff.2020.10386...
).

Carotenoids are widely known for their antioxidant capacity(5252 Meza-Herrera CA, Vargas-Beltran F, Tena-Sempere M, González-Bulnes A, Macias-Cruz U, Veliz-Deras FG. Short-term betacarotene supplementation positively affects ovarian activity and serum insulin concentrations in a goat model. J Endocrinol Invest. 2013;36(3):185-9. doi: 10.3275/8410
https://doi.org/10.3275/8410...
,6161 Hix LM, Lockwood SF, Bertram JS. Bioactive carotenoids: Potent antioxidants and regulators of gene expression. Redox Rep. 2004;9(4):181-91. doi: 10.1179/135100004225005967
https://doi.org/10.1179/1351000042250059...
,6262 Grune T, Lietz G, Palou A, Ross AC, Stahl W, Tang G, et al. B-Carotene is am important vitamin a source for humans. J Nutr. 2010;140:2268-85. doi: 10.3945/jn.109.119024
https://doi.org/10.3945/jn.109.119024...
) and for being natural precursors of vitamin A (retinol), a fat-soluble vitamin involved in cell division and differentiation, bone development and reproductive function(6262 Grune T, Lietz G, Palou A, Ross AC, Stahl W, Tang G, et al. B-Carotene is am important vitamin a source for humans. J Nutr. 2010;140:2268-85. doi: 10.3945/jn.109.119024
https://doi.org/10.3945/jn.109.119024...
,6363 Lopez-Flores NM, Meza-Herrera CA, Perez-Marin C, Blache D, Arellano-Rodríguez G, Zuñiga-Garcia S, et al. Precision betacarotene supplementation enhanced ovarian function and the LH release pattern in yearling crossbred anestrous goats. Animals. 2020;10(4):1-10. doi: 10.3390/ani10040659
https://doi.org/10.3390/ani10040659...
). The antioxidant effects of carotenoids were investigated in several in vivo and in vitro tests involving structures of the female reproductive system of different domestic species. As an example, in an in vivo study evaluating the effect of β-carotene supplementation on ovarian function, goats supplemented with 50 mg/day of β-carotene in association with the diet, for 34 days pre and 17 days post ovulation, indicated increased ovarian activity characterized by increase of the follicles population, ovulation rate, and total number of corpora lutea(5252 Meza-Herrera CA, Vargas-Beltran F, Tena-Sempere M, González-Bulnes A, Macias-Cruz U, Veliz-Deras FG. Short-term betacarotene supplementation positively affects ovarian activity and serum insulin concentrations in a goat model. J Endocrinol Invest. 2013;36(3):185-9. doi: 10.3275/8410
https://doi.org/10.3275/8410...
). In vitro, lycopene supplementation in the culture medium of ovarian fragments from aged hens, reduced oxidative stress through activation of antioxidants and the Nrf / HO-1 pathway, increasing cell proliferation and reducing apoptosis rates(77 Liu X, Lin X, Zhang S, Guo C, Li J, Mi Y, et al. Lycopene ameliorates oxidative stress in the aging chicken ovary via activation of Nrf2/HO-1 pathway. Aging. 2018;10(8):2016-36. doi: 10.18632/aging.101526
https://doi.org/10.18632/aging.101526...
). During bovine cumulus-oocyte complexes (COCs) in vitro maturation (IVM), the supplementation with lycopene, another carotenoid, reduced apoptosis rates and oocyte reactive oxygen species (ROS) levels, resulting in higher cleavage rates, as well as increased total trophectoderm cells and inner cell mass of embryos produced from in vitro fertilization(88 Residiwati G, Azari-Dolatabad N, Tuska HSA, Sidi S, Van Damme P, Benedetti C, et al. Effect of lycopene supplementation to bovine oocytes exposed to heat shock during in vitro maturation. Theriogenology. 2021;173:48-55. doi: 10.1016/j.theriogenology.2021.07.014
https://doi.org/10.1016/j.theriogenology...
).

Lycopene supplementation during IVM of bovine COCs also impacted blastocyst production with significantly higher rates and lower apoptotic cells ratio when compared to IVM groups treated without lycopene. In addition, lycopene-treated groups showed 296 differentially expressed genes after transcriptomic analysis, in which pathways associated with cell function, metabolism, DNA repair and anti-apoptosis were positively regulated in the lycopene group(99 Sidi S, Pascottini OB, Angel-Velez D, Azari-Dolatabad N, Pavani KC, Residiwati G, et al. Lycopene supplementation to serum-free maturation medium improves in vitro bovine embryo development and quality and modulates embryonic transcriptomic Profile. Antioxidants. 2022;344(11):3-18. doi: 10.3390/antiox11020344
https://doi.org/10.3390/antiox11020344...
).

Besides lycopene, the addition of carotenoids such as β-carotene and canthaxanthin was evaluated during IVM of murine and porcine oocytes, respectively. During murine IVM, β-carotene blocked the inhibition of oocyte maturation induced by Rosup, reagent that stimulates ROS production. Thus, β-carotene enhanced parthenogenetic activation of ROS-exposed mouse oocytes, reducing apoptosis levels, and restoring actin expression and cortical granule distribution in Rosup-exposed oocytes(6464 Yu S, Zhao Y, Feng Y, Zhang H, Li L, Shen W, et al. Β-Carotene improves oocyte development and maturation under oxidative stress in vitro. Vitr Cell Dev Biol - Anim. 2019;55(7):548-58. doi: 10.1007/s11626-019-00373-0
https://doi.org/10.1007/s11626-019-00373...
). The addition of canthaxanthin, in turn, increased cleavage and blastocyst formation rates, from parthenogenetically activated porcine oocytes, increasing glutathione levels, a water-soluble antioxidant recognized as the most important non-protein thiol in living systems, and dramatically reduced the ROS levels(6565 Taweechaipaisankul A, Jin JX, Lee S, Kim GA, Lee BC. The effects of canthaxanthin on porcine oocyte maturation and embryo development in vitro after parthenogenetic activation and somatic cell nuclear transfer. Reprod Domest Anim. 2016;51:870-6. doi: 10.1111/rda.12748
https://doi.org/10.1111/rda.12748...
).

Much of the positive effects achieved by the use of carotenoids in cell culture media or in animal feed, as nutritional supplements, is due to their antioxidant potential. It is well known that cancer, as well as chemotherapies and environmental pollutants, have been reported to promote a significant increase in EROS levels, acting as pro-oxidant factors for the rest of the body, affecting homeostasis and causing damage. In this sense, compounds such as carotenoids help to promote redox balance(6666 Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479-96. doi: 10.3109/10715761003667554
https://doi.org/10.3109/1071576100366755...
,6767 Al-Gubory KH. Environmental pollutants and lifestyle factors induce oxidative stress and poor prenatal development. Reproductive BioMedicine Online. 2014;(29):17-31. doi: 10.1016/j.rbmo.2014.03.002
https://doi.org/10.1016/j.rbmo.2014.03.0...
).

In addition to benefiting biological systems through their antioxidant potential, carotenoids have direct anticancer activity. In a study with an intraperitoneal model, tumor metastasis in murine with implanted ovarian cancer cells was attenuated by oral intake of lycopene, which significantly reduced the levels of pro-tumor factors such as ki67(6868 Holzapfel NP, Shokoohmand A, Wagner F, Landgraf M, Champ S, Holzapfel BM, et al. Lycopene reduces ovarian tumor growth and intraperitoneal metastatic load. Am J Cancer Res. 2017;7(6):1322-36.). In another study, oral administration of astaxanthin promoted apoptosis in DMH-induced murine colon cancer by modulating the expressions of nuclear factor-κB (NFκB), cyclooxygenase-2 (COX-2), metalloproteinase (MMP) 2 and 9, proliferating cell nuclear antigen (PCNA), and serine/threonine protein kinase (ERK), factors related to carcinogenesis(6969 Nagendraprabhu P, Sudhandiran G. Astaxanthin inhibits tumor invasion by decreasing extracellular matrix production and induces apoptosis in experimental rat colon carcinogenesis by modulating the expressions of ERK-2, NFkB and COX-2. Invest New Drugs. 2011;29(2):207-24. doi: 10.1007/s10637-009-9342-5
https://doi.org/10.1007/s10637-009-9342-...
). In vitro, lycopene induced apoptosis of human breast cancer cells(7070 Takeshima M, Ono M, Higuchi T, Chen C, Hara T, Nakano S. Anti-proliferative and apoptosis-inducing activity of lycopene against three subtypes of human breast cancer cell lines. Cancer Sci. 2014;105(3):252-7. doi: 10.1111/cas.12349
https://doi.org/10.1111/cas.12349...
) and reduced intracellular and mitochondrial ROS levels, as well as induced apoptosis of pancreatic cancer cells (Panc-1) by activation of caspase and increase of Bax(7171 Jeong Y, Lim JW, Kim H. Lycopene inhibits reactive oxugen species-mediated nf-kb signaling and induces apoptosis in pancreatic cancer cells. Nutrients. 2019;11(4):1-17. doi: doi:10.3390/nu11040762
https://doi.org/10.3390/nu11040762...
).

Melanin

Melanin is a general term for a group of heterogeneous pigments, generally insoluble in water, aqueous acid and common organic solvents that usually appear in black or dark brown coloration, and can also produce reddish or yellowish colors(4747 Arun G, Eyini M, Gunasekaran P. Characterization and biological activities of extracellular melanin produced by Schizophyllum commune (Fries). Indian J Exp Biol. 2015;53(6):380-7.). These pigments are produced by organisms in all domains of living beings, from bacteria to mammals(7272 Tran-Ly AN, Reyes C, Schwarze FWMR, Ribera J. Microbial production of melanin and its various applications. World J Microbiol Biotechnol [Internet]. 2020;36(11):1-9. Available from: https://doi.org/10.1007/s11274-020-02941-z
https://doi.org/10.1007/s11274-020-02941...
). Melanin biosynthesis in bacteria occurs by oxidative phenolic polymerization compounds, predominantly by two pathways, 1,8-dihydroxynaphthalene and 3,4-dihydroxyphenylalanine, resulting in different types of melanin: eumelanin, pheomelanin, allomelanin, pyomelanin, and neuromelanin(7373 Singh S, Nimse SB, Mathew DE, Dhimmar A, Sahastrabudhe H, Gajjar A, et al. Microbial melanin: Recent advances in biosynthesis, extraction, characterization, and applications. Biotechnol Adv [Internet]. 2021;53(5):107773. Available from: https://doi.org/10.1016/j.biotechadv.2021.107773
https://doi.org/10.1016/j.biotechadv.202...
). Melanins may exhibit a variety of functions in environmental and pathogenic bacteria, conferring adaptive advantages and increasing their suitability and survival under many stress conditions(7373 Singh S, Nimse SB, Mathew DE, Dhimmar A, Sahastrabudhe H, Gajjar A, et al. Microbial melanin: Recent advances in biosynthesis, extraction, characterization, and applications. Biotechnol Adv [Internet]. 2021;53(5):107773. Available from: https://doi.org/10.1016/j.biotechadv.2021.107773
https://doi.org/10.1016/j.biotechadv.202...
). Among all melanin biological activities, we highlight: the conference of resistance to thermal stress caused by radiation and oxidative stress occasioned by redox imbalance, and resistance to toxic compounds and heavy metals(4848 Pavan ME, López NI, Pettinari MJ. Melanin biosynthesis in bacteria, regulation and production perspectives. Appl Microbiol Biotechnol. 2020;104(4):1357-70. doi: 10.1007/s00253-019-10245-y
https://doi.org/10.1007/s00253-019-10245...
). These advantages confer to this substance, great potential of application as a natural antioxidant and anticancer compound.

Melanin is an antioxidant polymer that readily interacts with free radicals and other ROS, providing simple electrons transfer(4646 El-Naggar N, El-Ewasy SM. Bioproduction, characterization, anticancer and antioxidant activities of extracellular melanin pigment produced by newly isolated microbial cell factories Streptomyces glauscescens NEAE-H. Sci Rep. 2017;7:1-19. doi: 10.1038/srep42129
https://doi.org/10.1038/srep42129...
). In an in vitro study, melanin produced by Schizophyllum commune, a yeast, showed a dose-dependent effect on the inhibition of proliferation of human laryngeal epidermoid carcinoma cell lines (HEP-2) and high activity in the elimination of 2, 2-diphenyl-1-picrylhydrazyl free radicals at a concentration of 50 μg/mL(4747 Arun G, Eyini M, Gunasekaran P. Characterization and biological activities of extracellular melanin produced by Schizophyllum commune (Fries). Indian J Exp Biol. 2015;53(6):380-7.). In another study, melanin produced by Streptomyces glaucescen demonstrated potent in vitro cytotoxic activity against proliferation and survival of skin cancer cell line (HFB4), showing a mortality rate of 81.3% of cancer cells when exposed to a concentration of 100 μg/mL for 24 hours. Furthermore, it was shown to be highly safe by exhibiting low cytotoxicity in normal cells (human lung fibroblast and human amniotic cells) compared to usual chemotherapeutics such as 5-fluorouracil(4646 El-Naggar N, El-Ewasy SM. Bioproduction, characterization, anticancer and antioxidant activities of extracellular melanin pigment produced by newly isolated microbial cell factories Streptomyces glauscescens NEAE-H. Sci Rep. 2017;7:1-19. doi: 10.1038/srep42129
https://doi.org/10.1038/srep42129...
). In addition to the anticancer effect, melanin extracted from S. glaucescen exhibited antioxidant effect comparable to that of ascorbic acid. Along the same lines, researchers recently extracted melanin produced by Bacillus licheniformis and tested its effect in vitro on several cancer cell lines. They observed a promising anticancer effect of the pigment against breast cancer cell line (MCF-7), human hepatocellular carcinoma cell line (HepG2), and colon carcinoma cell (HCT116). Additionally, low cytotoxicity of melanin has been observed when used in vitro at low concentrations on healthy cells such as human fibroblasts [HFB4(7474 Gamal Shalaby AS, Ragab TIM, Helal MMI, Esawy MA. Optimization of Bacillus licheniformis MAL tyrosinase: in vitro anticancer activity for brown and black eumelanin. Heliyon [Internet]. 2019;5(5):e01657. Available from: https://doi.org/10.1016/j.heliyon.2019.e01657
https://doi.org/10.1016/j.heliyon.2019.e...
)].

Violacein

Violacein is a violet-colored bacterial pigment synthesized from tryptophan through a pathway involving the sequential action of five different enzymes (encoded by the genes vio A, B, C, D, and vio E). It is produced by the species Chromobacterium violaceum and Janthinobacterium lividum(7575 Matz C., Deines P, Boenigk J, Arndt H, Eberl L, Kjelleberg S, Ju¨rgens. Impact of violacein-producing bacteria on survival and feeding of bacterivorous nanoflagellates. Appl Environ Microbiol. 2004;70(3): 1593-9. doi: 10.1128/AEM.70.3.1593-1599.2004
https://doi.org/10.1128/AEM.70.3.1593-15...
), which are gram-negative bacteria found in terrestrial and aquatic environments, such as Negro River in Brazil(4444 Bromberg N, Dreyfuss JL, Regatieri C V., Palladino M V., Durán N, Nader HB, et al. Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor. Chem Biol Interact. 2010;186(1):43-52. doi: 10.1016/j.cbi.2010.04.016
https://doi.org/10.1016/j.cbi.2010.04.01...
). In vitro studies have indicated that violacein is characterized by its antibiotic(7676 Dodou HV., de Morais Batista AH, Sales GWP, de Medeiros SC, Rodrigues ML, Nogueira PCN, et al. Violacein antimicrobial activity on Staphylococcus epidermidis and synergistic effect on commercially available antibiotics. J Appl Microbiol. 2017;123(4):853-60. doi: 10.1111/jam.13547
https://doi.org/10.1111/jam.13547...
), antiprotozoal(7575 Matz C., Deines P, Boenigk J, Arndt H, Eberl L, Kjelleberg S, Ju¨rgens. Impact of violacein-producing bacteria on survival and feeding of bacterivorous nanoflagellates. Appl Environ Microbiol. 2004;70(3): 1593-9. doi: 10.1128/AEM.70.3.1593-1599.2004
https://doi.org/10.1128/AEM.70.3.1593-15...
), and antiviral(7777 Andrighetti-Fröhner CR, Antonio R V, Creczynski-Pasa TB, Barardi CRM, Simões CMO. Cytotoxicity and potential antiviral evaluation of violacein produced by Chromobacterium violaceum. Mem Inst Oswaldo Cruz. 2003;98(6):843-8. doi: 10.1590/s0074-02762003000600023
https://doi.org/10.1590/s0074-0276200300...
) therapeutic effects. This pigment has been reported to induce apoptosis in several cancer cell lines, indicating its use as a potential anticancer agent. The cytotoxicity of violacein for Ehrlich Ascites Tumor cells, for example, is mediated by a rapid (8-12 h) production of ROS and a decrease in intracellular glutathione levels, probably due to oxidative stress(4444 Bromberg N, Dreyfuss JL, Regatieri C V., Palladino M V., Durán N, Nader HB, et al. Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor. Chem Biol Interact. 2010;186(1):43-52. doi: 10.1016/j.cbi.2010.04.016
https://doi.org/10.1016/j.cbi.2010.04.01...
). In a human leukemia cell line (HL-60) violacein cytotoxicity was shown to be preceded by caspases activation, nuclear factor kappa-B (NF-kappaB) target genes transcription, and mitogen-activated protein kinase [MAP(7878 Ferreira CV, Bos CL, Versteeg HH, Justo GZ, Durán N, Peppelenbosch MP. Molecular mechanism of violacein-mediated human leukemia cell death. Blood. 2004;104(5):1459-64. doi: 10.1182/blood-2004-02-0594
https://doi.org/10.1182/blood-2004-02-05...
)]. In human colon cancer cell lines (Caco-2), violacein mediates ROS production, followed by caspase-3 activation, cytochrome C release, and calcium release into the cytosol, leading to Caco-2 cell death via the apoptosis pathway(7979 Carvalho DD, Costa FTM, Duran N, Haun M. Cytotoxic activity of violacein in human colon cancer cells. Toxicol Vitr. 2006;20(8):1514-21. doi: 10.1016/j.tiv.2006.06.007
https://doi.org/10.1016/j.tiv.2006.06.00...
). Another study found that the pigment produced by the species Janthinobacterium lividum was able to inhibit, in vitro and in vivo, head and neck carcinoma cell lines growth. In this study, violacein inhibited cell growth and induced autophagy and apoptosis, and its effect on the inhibition of cell proliferation pathways (ERK1 and ERK2), as well as increasing the Bax/Bcl-2 ratio linked to apoptosis, induction of p53 degradation, accumulation of NF-kappaB, and ROS production(8080 Masuelli L, Pantanella F, La Regina G, Benvenuto M, Fantini M, Mattera R, et al. Violacein, an indole-derived purple-colored natural pigment produced by Janthinobacterium lividum, inhibits the growth of head and neck carcinoma cell lines both in vitro and in vivo. Tumor Biol. 2016;37(3):3705-17. doi: 10.1007/s13277-015-4207-3
https://doi.org/10.1007/s13277-015-4207-...
) was observed. In an in vivo study in BALB/c mice, the intratumoral injection of 0.75 mg/kg violacein dissolved in DMSO and diluted in PBS, as well as the injection of 1 mg/kg during 35 days were safe and did not alter the hematometric levels(4444 Bromberg N, Dreyfuss JL, Regatieri C V., Palladino M V., Durán N, Nader HB, et al. Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor. Chem Biol Interact. 2010;186(1):43-52. doi: 10.1016/j.cbi.2010.04.016
https://doi.org/10.1016/j.cbi.2010.04.01...
).

Besides inducing apoptosis in cancer cells, violacein promoted morphological alterations in brain tumor cell lines (U87) regulating their migratory capacity, and interfering in the metastatic process(8181 Mehta T, Vercruysse K, Johnson T, Ejiofor AO, Myles E, Quick QA. Violacein induces p44/42 mitogen-activated protein kinase-mediated solid tumor cell death and inhibits tumor cell migration. Mol Med Rep. 2015;12(1):1443-8. doi: 10.3892/mmr.2015.3525
https://doi.org/10.3892/mmr.2015.3525...
). Finally, an in vitro study found that violacein acts synergistically with the chemotherapeutic 5-fluorouracil, increasing cytotoxicity and apoptosis induction, as well as interfering with Akt-mediated signal transduction in human colorectal cancer cell lines(4545 Kodach LL, Bos CL, Durán N, Peppelenbosch MP, Ferreira C V., Hardwick JCH. Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells. Carcinogenesis. 2006;27(3):508-16. doi: 10.1093/carcin/bgi307
https://doi.org/10.1093/carcin/bgi307...
).

Prodiginines

Among the class of bacterial pigments discovered and widely studied over the years, prodiginines can be considered the most remarkable, curious and important of this category. The name "prodiginine", associated with "prodigy, miracle", has its origin in its supposed connection with reports dating back to the year 322 BC, when Macedonian soldiers reported the appearance of supposed drops of blood inside the bread used for food, an event considered prophetic by the clairvoyants of Emperor Alexander the Great. The knowledge and study of these pigments also sought to justify miraculous events that occurred more than 700 years ago, such as the Miracle of Bolsena, origin of the Corpus Christi celebration, when supposed drops of blood were observed on the host during a mass celebrated by a priest who was struggling with a lack of faith(8282 Fürstner A. Chemistry and biology of roseophilin and the prodigiosin alkaloids: A survey of the last 2500 years. Angew Chem Int Ed. 2003;42(31):3582-603. doi: 10.1002/anie.200300582
https://doi.org/10.1002/anie.200300582...
).

In contrast to the rumors involving this class of pigments, which are formed by bacterial colonies resembling blood droplets, the prodiginines class comprises a group of red pigments, alkaloids, structurally characterized as heterocyclic tripyrroles, i.e., they contain three interconnected pyrrole rings [A, B, and C(4949 Darshan N, Manonmani HK. Prodigiosin and its potential applications. J Food Sci Technol. 2015;52(9):5393-407. doi: 10.1007/s13197-015-1740-4
https://doi.org/10.1007/s13197-015-1740-...
)]. This group of pigments includes prodigiosin, metacycloprodigiosin, undecylprodigiosin, nonylprodigiosin, cycloprodigiosin, cyclonylprodigiosin, and butylcycloheptylprodigiosin(8383 Elahian F, Moghimi B, Dinmohammadi F, Ghamghami M, Hamidi M, Mirzaei SA. The anticancer agent prodigiosin is not a multidrug resistance protein substrate. DNA Cell Biol. 2013;32(3):90-7. doi: 10.1089/dna.2012.1902
https://doi.org/10.1089/dna.2012.1902...
,8484 Liu Y, Zhou H, Ma X, Lin C, Lu L, Liu D, et al. Prodigiosin inhibits proliferation, migration, and invasion of nasopharyngeal cancer cells. Cell Physiol Biochem. 2018;48(4):1556-62. doi: 10.1159/00049227
https://doi.org/10.1159/00049227...
). Conveniently, due to the isoforms similarity of these substances, it has become a consensus to use the term "prodiginine" to characterize the class of alkaloids, and "prodigiosin" to refer to the particular names of the red or magenta pigments(8585 Silva A, Guimarães L, Ferreira E, Torres M, Silva A., Branco P, et al. Bioprospecting anticancer compounds from the marine-derived Actinobacteria Actinomadura sp. collected at the Saint Peter and Saint Paul Archipelago (Brazil). J Braz Chem Soc. 2017;28(3):465-74. doi: 10.21577/0103-5053.20160297
https://doi.org/10.21577/0103-5053.20160...
). Prodiginines are secondary metabolites that were first extracted and characterized from the gram-negative Serratia marcescens(8484 Liu Y, Zhou H, Ma X, Lin C, Lu L, Liu D, et al. Prodigiosin inhibits proliferation, migration, and invasion of nasopharyngeal cancer cells. Cell Physiol Biochem. 2018;48(4):1556-62. doi: 10.1159/00049227
https://doi.org/10.1159/00049227...
). In addition to S. marcescens, the pigment has also been isolated from several gram-positive and gram-negative species(8383 Elahian F, Moghimi B, Dinmohammadi F, Ghamghami M, Hamidi M, Mirzaei SA. The anticancer agent prodigiosin is not a multidrug resistance protein substrate. DNA Cell Biol. 2013;32(3):90-7. doi: 10.1089/dna.2012.1902
https://doi.org/10.1089/dna.2012.1902...
,8686 Gulani C, Bhattacharya S, Das A. Assessment of process parameters influencing the enhanced production of prodigiosin from Serratia marcescens and evaluation of its antimicrobial, antioxidant and dyeing potentials. Malays J Microbiol. 2012;8(2):116-22. doi: 10.21161/mjm.03612
https://doi.org/10.21161/mjm.03612...
). Between this pigment-producing species, S. marcescens stands out for being easy to cultivate, providing massive production of this bioactive product(8787 Sudhakar C, Shobana C, Selvankumar T, Selvam K. Prodigiosin production from Serratia marcescens strain CSK and their antioxidant, antibacterial, cytotoxic effect and in silico study of caspase-3 apoptotic protein. Biotechnol Appl Biochem. 2021;1-14. doi: 10.1002/bab.2261
https://doi.org/10.1002/bab.2261...
).

Prodigiosins are pH-sensitive, photosensitive, insoluble in water, sparingly soluble in alcohol and ether, and soluble in chloroform, methanol, acetonitrile, and DMSO(8888 Wang F, Luo H, Song G, Liu C, Wang J, Xu J, et al. Prodigiosin found in Serratia marcescens y2 initiates phototoxicity in the cytomembrane. Electron J Biotechnol. 2013;16(4):1-9. doi: 10.2225/vol16-issue4-fulltext-7
https://doi.org/10.2225/vol16-issue4-ful...

89 Ji S, Sun R, Xu K, Man Z, Ji J, Pu Y, et al. Prodigiosin induces apoptosis and inhibits autophagy via the extracellular signal-regulated kinase pathway in K562 cells. Toxicol Vitr [Internet]. 2019;60(11):107-15. Available from: https://doi.org/10.1016/j.tiv.2019.05.003
https://doi.org/10.1016/j.tiv.2019.05.00...
-9090 Zhao Y, Cheng Q, Shen Z, Fan B, Xu Y, Cao Y, et al. Structure of prodigiosin from Serratia marcescens njzt-1 and its cytotoxicity on tsc2-null cells. Food Sci Technol. 2021;41:189-96. doi: 10.1590/fst.35719
https://doi.org/10.1590/fst.35719...
). Although the mechanism by which these compounds act, is complex and probably multifactorial, a wide variety of studies have demonstrated important pigment-associated properties. Prodigiosins have exhibited varied properties, namely: 1- antiviral, specifically inhibiting at least the NF-kappaB and Akt signaling pathways, which promotes accelerated cell death in cells infected with Herpes simplex virus(9191 Suryawanshi RK, Koujah L, Patil CD, Ames JM, Agelidis A, Yadavalli T, et al. Bacterial pigment prodigiosin demonstrates a unique antiherpesvirus activity that is mediated through inhibition of prosurvival signal transducers. J Virol. 2020;94(13):1-30. doi: 10.1128/JVI.00251-20
https://doi.org/10.1128/JVI.00251-20...
); 2- antimicrobial activity, with 30% inhibitory activity for Candida albicans, Escherichia coli, and Staphylococcus aureus(9292 Suryawanshi RK, Patil CD, Koli SH, Hallsworth JE, Patil S V. Antimicrobial activity of prodigiosin is attributable to plasma-membrane damage. Nat Prod Res [Internet]. 2017;31(5):572-7. Available from: http://dx.doi.org/10.1080/14786419.2016.1195380
http://dx.doi.org/10.1080/14786419.2016....
); 3- anti-inflammatory activity, identified as a potential COX-2 protein inhibitor(9393 Krishna PS, Vani K, Prasad MR, Samatha B, Hima Bindu NSVSL, Singara Charya MA, et al. In -silico molecular docking analysis of prodigiosin and cycloprodigiosin as COX-2 inhibitors. Springerplus. 2013;2(1):1-6. http://www.springerplus.com/content/2/1/172
http://www.springerplus.com/content/2/1/...
); and 4- antioxidant activity, with a DPPH radical scavenging potential of ~78% and ABTS radical scavenging potential of ~71% at a concentration of 500 μg/mL(8787 Sudhakar C, Shobana C, Selvankumar T, Selvam K. Prodigiosin production from Serratia marcescens strain CSK and their antioxidant, antibacterial, cytotoxic effect and in silico study of caspase-3 apoptotic protein. Biotechnol Appl Biochem. 2021;1-14. doi: 10.1002/bab.2261
https://doi.org/10.1002/bab.2261...
).

Parallel to the properties quoted above, prodigiosin exhibited relevant and potent anticancer action against several cancer cell lines, with distinct mechanisms. In leukemia cell line (K562), it inhibited proliferation, increased the rate of ROS, induced apoptosis, probably by inducing an increase of pro-apoptotic proteins, caspase-3-cleaved, 8 and 9, and inhibited autophagy. It was also identified that the activated ERK cascade plays a primary role in prodigiosin-induced apoptosis in K562 cells(8989 Ji S, Sun R, Xu K, Man Z, Ji J, Pu Y, et al. Prodigiosin induces apoptosis and inhibits autophagy via the extracellular signal-regulated kinase pathway in K562 cells. Toxicol Vitr [Internet]. 2019;60(11):107-15. Available from: https://doi.org/10.1016/j.tiv.2019.05.003
https://doi.org/10.1016/j.tiv.2019.05.00...
). In hematopoietic cancer cell lines (Jurkat-derived T lymphocyte leukemia cells, NOS-derived murine myeloma model cell line, HL-60, RAMOS-derived Burkitt lymphoma cells), prodigiosin affected cell proliferation rates and apoptosis, which was characterized by dose-dependent decrease in the number of viable cells, and increase in apoptotic cells in all cancer cell lines studied(9494 Montaner B, Navarro S, Piqué M, Vilaseca M, Martinell M, Giralt E, et al. Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. Br J Pharmacol. 2000;131(3):585-93. doi: 10.1038/sj.bjp.0703614
https://doi.org/10.1038/sj.bjp.0703614...
).

Another cancer cell line studied was human mucoepidermoid lung carcinoma (NCHI-292), HEP-2, MCF-7 and HL-60, in which the pigment isolated from Serratia marcescens produced significant cytotoxic effects in all cell lines, with an inhibitory concentration (IC50) of 3.6, 3.4, 5.1 and 1.7 µg/mL, respectively(9595 Lapenda JCL, Alves VP, Adam ML, Rodrigues MD, Nascimento SC. Cytotoxic effect of prodigiosin, natural red pigment, isolated from Serratia marcescens UFPEDA 398. Indian J Microbiol [Internet]. 2020;60(2):182-95. Available from: https://doi.org/10.1007/s12088-020-00859-6
https://doi.org/10.1007/s12088-020-00859...
). In cervical cancer cell line (HeLa), prodigiosin inhibited proliferation and induced apoptosis, thanks to upregulation of Bax and caspase-3, with an IC50 of 2.1, 1.2 and 0.5 μg/mL after 24, 48 and 72 h of exposure(9696 Lin P Bin, Shen J, Ou PY, Liu LY, Chen ZY, Chu FJ, et al. Prodigiosin isolated from Serratia marcescens in the Periplaneta americana gut and its apoptosis‑inducing activity in HeLa cells. Oncol Rep. 2019;41(6):3377-85. doi: 10.3892/or.2019.7089
https://doi.org/10.3892/or.2019.7089...
). Additionally, the association of prodigiosin with different substances was also effective. For example, in association with Zelavespib (PU-H71), an experimental Hsp90 chaperone inhibitor, prodigiosin alone or in combination up-regulated the expression of Bax without affecting that of Bcl-2. The combination also increased the expression of caspase-3, 8 and 9, inducing apoptosis and inhibiting adhesion of breast adenocarcinoma cell lines [MDA-MB-231(1515 Anwar MM, Shalaby M, Embaby AM, Saeed H, Agwa MM, Hussein A. Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights. Sci Rep [Internet]. 2020;10(1):1-15. Available from: https://doi.org/10.1038/s41598-020-71157-w
https://doi.org/10.1038/s41598-020-71157...
)]. Similar effects were obtained with the association between prodigiosin and cisplatin, in which prodigiosin increased the sensitivity of cisplatin-resistant urothelial carcinoma cell lines(9797 Berning L, Schlütermann D, Friedrich A, Berleth N, Sun Y, Wu W, et al. Prodigiosin sensitizes sensitive and resistant urothelial carcinoma cells to cisplatin treatment. Molecules. 2021;26(5):1-17. doi: 10.3390/molecules26051294
https://doi.org/10.3390/molecules2605129...
). Interestingly, despite being effective against a wide variety of cancer cells, prodigiosin has little, if any, cytotoxicity against normal cells(1515 Anwar MM, Shalaby M, Embaby AM, Saeed H, Agwa MM, Hussein A. Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): preclinical insights. Sci Rep [Internet]. 2020;10(1):1-15. Available from: https://doi.org/10.1038/s41598-020-71157-w
https://doi.org/10.1038/s41598-020-71157...
,1919 Guryanov I, Naumenko E, Akhatova F, Lazzara G, Cavallaro G, Nigamatzyanova L, et al. Selective cytotoxic activity of prodigiosin@halloysite nanoformulation. Front Bioeng Biotechnol. 2020;8:1-13. doi: 10.3389/fbioe.2020.00424
https://doi.org/10.3389/fbioe.2020.00424...
,9494 Montaner B, Navarro S, Piqué M, Vilaseca M, Martinell M, Giralt E, et al. Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. Br J Pharmacol. 2000;131(3):585-93. doi: 10.1038/sj.bjp.0703614
https://doi.org/10.1038/sj.bjp.0703614...
).

Pyocyanin

Pyocyanin is a secondary redox active metabolite and an important virulence factor of gram-negative bacteria Pseudomonas spp(9898 Ashour EA, Farsi RM, Alaidaroos BA, Abdel-Moneim AME, El-Saadony MT, Osman AO, et al. Impacts of dietary supplementation of pyocyanin powder on growth performance, carcase traits, blood chemistry, meat quality and gut microbial activity of broilers. Ital J Anim Sci [Internet]. 2021;20(1):1357-72. Available from: https://doi.org/10.1080/1828051X.2021.1924087
https://doi.org/10.1080/1828051X.2021.19...
). It is a bluish pigment that composes a family of tricyclic compounds, phenazines, and may exist in oxidized or reduced form, the latter being unstable and highly reactive with molecular oxygen(1717 Marrez DA, Mohamad HS. Biological activity and applications of pyocyanin produced by Pseudomonas aeruginosa. Open Access J Biomed Sci. 2020;1(4):140-4. doi: 10.38125/OAJBS.000133
https://doi.org/10.38125/OAJBS.000133...
). Unlike other pigments with antioxidant action, pyocyanin seems to induce oxidative stress in cellular systems and, for this reason, may induce cytotoxicity in cancer cells through the generation of ROS and, then, progressive cellular oxidative damage(9999 Moayedi A, Nowroozi J, Akhavan Sepahy A. Cytotoxic effect of pyocyanin on human pancreatic cancer cell line (Panc-1). Iran J Basic Med Sci. 2018;21(8):794-9. doi: 10.22038/IJBMS.2018.27865.6799
https://doi.org/10.22038/IJBMS.2018.2786...
).

There is a consensus that balanced ROS levels are involved in the processes of tumor formation, maintenance, and progression(100100 Kumari S, Badana AK, Murali Mohan G, Shailender G, Malla RR. Reactive oxygen species: A key constituent in cancer survival. biomarker insights. 2018;13:1-9. doi: 10.1177/1177271918755391
https://doi.org/10.1177/1177271918755391...
). ROS disbalance, characterizing an oxidative stress induced by chemotherapeutic drugs, is associated with tumor depletion(6666 Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44(5):479-96. doi: 10.3109/10715761003667554
https://doi.org/10.3109/1071576100366755...
), since oxidative stress induces lipid peroxidation, generating numerous electrophilic aldehydes that can attack several cellular targets(101101 Conklin KA. Chemotherapy-associated oxidative stress: Impact on chemotherapeutic effectiveness. Integr Cancer Ther. 2004;3(4):294-300. doi: 10.1177/1534735404270335
https://doi.org/10.1177/1534735404270335...
). Hence, the unbalanced increase in ROS associated with the accumulation of DNA damage, senescence, and cell death induced by agents such as pyocyanin may be a strategy for the depletion of growing tumors(102102 Colavitti R, Finkel T. Reactive oxygen species as mediators of cellular senescence. IUBMB Life. 2005;57:277-81. doi: 10.1080/15216540500091890
https://doi.org/10.1080/1521654050009189...
). On the other hand, the pro- or antioxidant effect of pyocyanin may be more related to its concentration and bioavailability, since in one study the in vitro free radical scavenging activity of pyocyanin was higher than that of ascorbic acid. In the same study, the substance isolated from Pseudomonas aeruginosa, did not significantly affect the viability of human fibroblasts, even at high concentrations (100 µg/mL) indicating, for example, safety of its use for food manufacturing, since it has antibiofilm activity against food pathogens such as Salmonella enteriditis and Vibrio diabolicus(103103 Laxmi M, Bhat SG. Characterization of pyocyanin with radical scavenging and antibiofilm properties isolated from Pseudomonas aeruginosa strain BTRY1. 3 Biotech. 2016;6(1):1-5. doi: 10.1007/s13205-015-0350-1
https://doi.org/10.1007/s13205-015-0350-...
).

The low cytotoxicity of pyocyanin in normal cells, combined with its anticancer property, places it in the Hall of bacterial pigments acting as natural anticancer compounds. The dose-dependent in vitro cytotoxic effects of pyocyanin were first reported in human hepatoma cells [HepG2(104104 Zhao J, Wu Y, Alfred AT, Wei P, Yang S. Anticancer effects of pyocyanin on HepG2 human hepatoma cells. Lett Appl Microbiol. 2014;58:541-8. doi: 10.1111/lam.12224
https://doi.org/10.1111/lam.12224...
)] and against the Panc-1(9999 Moayedi A, Nowroozi J, Akhavan Sepahy A. Cytotoxic effect of pyocyanin on human pancreatic cancer cell line (Panc-1). Iran J Basic Med Sci. 2018;21(8):794-9. doi: 10.22038/IJBMS.2018.27865.6799
https://doi.org/10.22038/IJBMS.2018.2786...
) cell line. Similar to other bacterial pigments, pyocyanin induces cell apoptosis, probably due to increased ROS, DNA damage, activation of caspase-3, and acceleration of cell senescence and apoptosis(104104 Zhao J, Wu Y, Alfred AT, Wei P, Yang S. Anticancer effects of pyocyanin on HepG2 human hepatoma cells. Lett Appl Microbiol. 2014;58:541-8. doi: 10.1111/lam.12224
https://doi.org/10.1111/lam.12224...
,105105 Muller M. Premature cellular senescence induced by pyocyanin, a redox-active Pseudomonas aeruginosa toxin. Free Radic Biol Med. 2006;41(11):1670-7. doi: 10.1016/j.freeradbiomed.2006.09.004
https://doi.org/10.1016/j.freeradbiomed....
). A brief summary with the main pigments addressed in this review, including pyocyanin, diverse pharmacological potential, as well as anticancer potential in distinct cancer cell lines is presented in table 2.

Future prospects and limitations

This review highlights the relevance to the study and practical applications of bacterial pigments. Microorganisms, and more specifically bacteria, are endless sources of these and other little-known bioactive compounds with vast pharmacological potential. Therefore, these pigments may contribute to the development of new therapeutic approaches in cancer treatment, as an alternative to reduce the negative effects of highly cytotoxic chemotherapeutics, or as adjuvants to chemotherapies. In addition, the domain of microorganisms manipulation associated with advances in genetic engineering allows considerable advances today, as well as for the future.

Identification, isolation and study of these and other bacterial pigments and bioactive metabolites are important alternatives for the generation of new anticancer drugs that present fewer side effects, i.e., greater selectivity against cancer cells and less cytotoxicity for normal cells. Among the side effects of chemotherapeutic protocols currently used for the treatment of cancer, we can highlight reproductive disorders, such as premature ovarian failure. However, despite advances in studies for the potential use of bacterial pigments as anticancer drugs, few have tested the effect of these pigments on the female reproductive system, gonads, gametes and embryos. In this sense, the use of animal models to study the reproductive toxicity of these substances is a valuable alternative, since the available biotechnologies enable to obtain most of the necessary biological material, following ethical research principles. Studies of in vitro culture of ovarian follicles, in vitro gametes maturation and in vitro embryos production can be used as tools to verify the pigments effects on females reproduction processes.

Table 2
Diverse pharmacological potential and anticancer potential of the main categories of bacterial pigments

Conclusion

The prospection for large-scale production of natural bioactive compounds extracted from microorganisms, such as bacterial pigments, is one of the great alternatives for obtaining substances with high potential for industrial and pharmaceutical application. In this sense, given the scarcity of in vitro and in vivo studies evaluating the effects of these substances on the female reproductive system, new investigations regarding the impact of these promising pigments on the development of ovarian follicles, gametes and embryos, are of great importance.

Acknowledgments

To professor Jonatan M. Del S. Velarde, for the appreciation and revision of the textual elements of this article, in its English version.

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Publication Dates

  • Publication in this collection
    24 Oct 2022
  • Date of issue
    2022

History

  • Received
    30 May 2022
  • Accepted
    22 Aug 2022
  • Published
    21 Sept 2022
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