Exploring the chemotherapeutic potential of five plant species through in vitro screening

[Explorando o potencial quimioterápico de cinco espécies de plantas por meio de triagem in vitro]

ABSTRACT

Cancer is a group of diseases characterized by uncontrolled proliferation and spread of abnormal cells. Among the commonly used antineoplastic treatments, chemotherapy is one of the most frequent. In searching for new antineoplastic drugs, finding more effective and selective drugs becomes increasingly necessary. Analysis by phenotypic screening can identify promising compounds in cancer chemotherapy. In this work, hydroalcoholic extracts of Plumbago auriculata Lam., Plumbago scandens L., Cestrum axillare Vell., Jatropha gossypiifolia L. and Jatropha multifida L. were screened for cytotoxic effect by MTT on glioblastoma (U-87 MG), colorectal carcinoma (RKO-AS45-1) and lung epithelial cell (WI-26 VA4) cell lines. After exposure to the extracts for 24, 48, and 72 hours, the extract of P. scandens exhibited the highest cytotoxicity in all cell lines. The extracts of the other plant species could not reduce cell survival to less than 50% at any cell line at the concentrations and exposure times. In conclusion, hydroalcoholic extract of P. scandens was highly cytotoxic to tumor cells, making it a promising tool in cancer chemotherapy. Further studies are needed to explore the isolated compounds as cancer chemotherapeutic agents.

Keywords:
antineoplastic drugs; cytotoxicity; Cestrum axillare; Jatropha; Plumbago

RESUMO

O câncer é um grupo de doenças caracterizadas pela proliferação e disseminação descontroladas de células anormais. Entre os tratamentos antineoplásicos comumente utilizados, a quimioterapia é um dos mais frequentes. Na busca por novos tratamentos antineoplásicos, encontrar medicamentos mais eficazes e seletivos torna-se cada vez mais necessário. A análise por triagem fenotípica pode identificar compostos promissores na quimioterapia do câncer. Neste trabalho, extratos hidroalcoólicos de Plumbago auriculata Lam., Plumbago scandens L., Cestrum axillare Vell., Jatropha gossypiifolia L. e Jatropha multifida L. foram testados quanto ao efeito citotóxico por MTT em linhas celulares de glioblastoma (U-87 MG), carcinoma colorretal (RKO-AS45-1) e células epiteliais pulmonares (WI-26 VA4). Após exposição por 24, 48 e 72 horas, o extrato de P. scandens exibiu a maior citotoxicidade em todas as linhas celulares. Os extratos das outras espécies de plantas não foram capazes de reduzir a sobrevivência celular para menos de 50% em nenhuma linhagem celular nas concentrações e nos tempos de exposição avaliados. Em conclusão, o extrato hidroalcoólico de P. scandens foi altamente citotóxico para células tumorais, tornando-o uma ferramenta promissora para a quimioterapia do câncer. Mais estudos são necessários para explorar os compostos isolados do extrato como agentes quimioterápicos do câncer.

Palavras-chave:
drogas antineoplásicas; citotoxicidade; Cestrum axillare; Jatropha; Plumbago

INTRODUCTION

Neoplasms are among the leading causes of death worldwide, being responsible for almost 10 million deaths in 2022 (Global Cancer Observatory, 2025 ). In Brazil, the estimate for each year of the 2023-2025 triennium indicates the occurrence of around 704 thousand new cancer cases (Santos et al., 2023). Despite the benefits, treatment with antineoplastic drugs involves different side effects, such as mouth sores, nausea and vomiting, hair loss, diarrhea, sensitive skin, and even infertility. Furthermore, multiple factors can compromise chemotherapy treatment through different mechanisms (Anand et al., 2022). Therefore, searching for new antineoplastic drugs becomes increasingly necessary and aims to find more effective and selective drugs.

About 60% of anticancer compounds available to cancer patients were obtained from plant, marine, and microorganism sources. The positive effect of plants on cancer treatment has been widely studied, and various plant secondary metabolites have shown promising antitumor activity against cancer cell lines (Tauro et al., 2024). The significant success achieved so far with using bioactive natural compounds as chemotherapeutic alternatives has generated a constant increase in the research of new molecules (Elekofehinti et al., 2021).

Species from the Plumbaginaceae family, such as Plumbago scandens L. and Plumbago auriculata Lam., have been widely explored due to their bioactive compounds. These shrubs with white and purple flowers, respectively, are found mainly in the coastal region of Brazil. Among other compounds, Plumbago contains naphthoquinone plumbagin, which has numerous pharmacological properties (Thakor and Janathia, 2022).

Jatropha multifida L., Euphorbiaceae family, has been popularly used to treat various disorders, and initial research reveals that this plant species has antioxidants, antibacterial, anti-inflammatory, antifungal, gastroprotective, healing, analgesic, immunomodulatory activities, among others (Dah-Nouvlessounon et al., 2023). In addition to J. multifida, secondary metabolites from Jatropha gossypiifolia L. have been studied for medicinal purposes due to their anti-inflammatory and anticancer potential (Wu et al., 2019). Another plant with promising therapeutic potential is Cestrum axillare Vell. (syn. Cestrum laevigatum Schltdl.), from Solanaceae family, but its hepatotoxicity must be considered since plants of this genus are responsible for causing acute liver necrosis in ruminants (Marinho et al., 2018).

The present study aimed to evaluate the in vitro chemotherapeutic potential of C. axillare, J. gossypiifolia, J. multifida, P. auriculata, and P. scandens, using a phenotypic screening model of colorectal carcinoma, human glioblastoma, and non-tumor cell lines.

MATERIAL AND METHODS

Fresh leaves of Cestrum axillare Vell., Jatropha gossypiifolia L., Jatropha multifida L., Plumbago auriculata Lam., and Plumbago scandens L. were collected at the Medicinal and Toxic Plants Garden at the Veterinary School, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil. The leaves were dried, crushed, and then mixed with absolute ethanol. They were subsequently placed in a sonicator bath for 20 minutes and subjected to maceration for approximately 48 hours. The extraction process was repeated twice, separating the supernatant by filtration. The solvent was removed from the extract under reduced pressure in a rotary evaporator at a maximum temperature of 50°C. The ethanolic residue was solubilized in water, filtered, and fractionated with hexane. The aqueous fraction obtained after fractionation was subjected again to the rotary evaporator to eliminate residual hexane. The residual aqueous portion was filtered through a 0.22µm syringe filter.

The extracts were aliquoted into 15mL polypropylene tubes and lyophilized. The lyophilized contents of the extracts of P. auriculata, J. multifida, and J. gossypiifolia were diluted in PBS 1X. The extracts of C. axillare and P. scandens were diluted in a solution of dimethyl sulfoxide (DMSO) and PBS 1X in a dilution of 1:5. Final concentrations of the extracts in relation to the amount of plant per volume of culture medium were: C. axillare - 2.325g/mL; J. gossypiifolia - 3.145g/mL; J. multifida - 3.242g/mL; P. auriculata - 2.608g/mL; and P. scandens - 2.398g/mL.

For the cytotoxicity assay, cell lines RKO-AS45-1 (RRID:CVCL_3786) colorectal carcinoma, U-87 MG (RRID:CVCL_0022) glioma, WI-26 VA4 (RRID:CVCL_2758) SV40 virus transformed derivative of WI-26 lung fibroblast used as a non-tumor cell (control) were obtained from ATCC® (American Type Culture Collection). Cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM - GIBCO®, cat. 12100- 046) supplemented with 10% Fetal Bovine Serum (FBS) (GIBCO®, cat. 12657-029) and 1% Pen-Strep solution 100X (10,000U/mL- Penicillin and 10mg/mL- Streptomycin - LGC Biotechnology®, cat. BR30110-01). Incubation was carried out in a humidified incubator at 37°C with 5% CO₂ (Thermo Fisher Scientific, Waltham, MA, USA). The subculture procedure was performed using a 0.25% (w/v) Trypsin-0.53mM EDTA solution in accordance with ATCC guidelines. Cell viability was evaluated with Trypan blue staining before each experiment. Only cell suspensions with >95% cell viability (passage numbers: 3-5) were acceptable for experiments.

The cytotoxicity assessment assay by incorporation of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was used to determine the cell viability and calculate the IC₅₀ concentration (mean inhibitory concentration). For the assay, 1x10⁵ cells per well were cultured in 96-well plates for all cell lines (RKO-AS45-1, U-87 MG, and WI-26 VA4). The plates were incubated in a humidified chamber at 37°C and with 5% CO₂ for up to 24 hours until the cell monolayer reached confluence.

The cells were treated with three different dilutions of the extracts: C1-10^-2, C2-10^-3, and C3-10^-4. Dilutions were performed in DMEM high-glucose medium supplemented with 1% FBS and 1% Pen-Strep solution 100X. Positive, negative, and vehicle controls were used to ensure assay performance. Hydrogen peroxide (1 mmol) was used as the positive control for cytotoxicity. Untreated cells were the negative control (blank). The vehicle control was done by adding 1% of PBS 1X to J. gossypiifolia, J. multifida, and P. auriculata extracts and 0.75% of PBS+0.25% DMSO for C. axillare and P. scandens extracts.

Cells were incubated at 37°C with 5% CO₂ for 24, 48, and 72 hours. Following the exposure periods, the supernatant was aspirated, wells were rinsed with a 1X PBS solution, then MTT solution (0.5mg/mL) was added, and the plates were incubated for an additional 3 hours. At the end of the incubation, the plates were centrifuged at 1,200 rpm for 10 minutes. After removing the supernatant, 50µL of DMSO was added to solubilize the formazan crystals. Subsequently, the plates were analyzed using a Multiskan SkyHigh microplate spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) at a wavelength of 550nm.

Data from cell viability was expressed as mean ±SEM (standard error of the mean) of nine replicates (three replicates repeated three times). The results were normalized by the respective values of vehicle controls (Cao et al., 2018; Zhang et al., 2021) according to the formula:

$\%Cellviability=(averageabsorbanceoftreatedcells/averageabsorbanceofvehiclecontrol)x100$

The IC50 value represents the dose that inhibits cell viability by 50%. This value was determined using Dr Fit software 1.042 (Di Veroli et al., 2015). The Selectivity Index (TI) was determined by IC50 against normal cells/IC50 against tumor cells.

Statistical analysis was conducted using a two-way ANOVA followed by Bonferroni post-test with comparisons between blank and treatments GraphPad Prism 5.0 (GraphPad, San Diego, CA).

RESULTS

The activities of P. scandens extract at concentrations C1, C2 and C3 are shown in Figure 1. The P. scandens extract at concentration C1 induced a significant cytotoxic effect across all exposure times (24, 48, and 72 hours) in the cell lines RKO-AS45-1. P. scandens extract at concentration C1 induced a significant cytotoxic effect against cell line U-87 MG within 24 hours of treatment.

Figure 1
Cytotoxic effect of Plumbago scandens extract in the cell lines RKO-AS45-1 (a), U-87 MG (b), and WI-26 VA4 (c) after 24, 48, and 72 hours. Data were normalized to the respective vehicle control values and are presented as the mean ± SEM from nine replicates. **p<0.01,***p<0.001, ****p<0.0001.

As shown in Table 1, The IC50 of P. scandens extract was determined for all cell lines after 24 hours of treatment. The cytotoxic activity against tumor cell lines was nearly four times higher in RKO-AS45-1 and five times higher in U-87 MG compared to the normal WI-26 VA4 cells, indicating considerable tumor selectivity.

When exposed to the P. auriculata extract at all concentrations, the cell line U-87 MG exhibited a significant decrease in survival after 24 hours of exposure (Fig. 2).

Cytotoxic effects of J. gossypiifolia extract were detected at C1 after 72 hours in the RKO-AS45-1 cell line and at the concentration C1 with 48 and 72 hours in WI-26 VA4. (Fig. 3).

Table 1
Determination of IC50 and Selectivity Index (SI) of the Plumbago scandens extract in the cell lines RKO-AS45-1, U-87 MG e WI-26 VA4

Cell lines	IC50 (24 hours)	SI
RKO-AS45-1	5.16 mg/mL	3.91
U-87 MG	4.03 mg/mL	5.01
WI-26 VA4	20.2 mg/mL	1.00

• IC50: Inhibitory Concentration of 50%; SI: Selectivity Index

Figure 2
Cytotoxic effect of Plumbago auriculata extract in the cell lines RKO-AS45-1 (a), U-87 MG (b), and WI-26 VA4 (c) after 24, 48, and 72 hours. Data were normalized to the respective vehicle control values and are presented as the mean ± SEM from nine replicates. *p<0.05, **p<0.01.

Figure 3
Cytotoxic effect of Jatropha gossypiifolia extract in the cell lines RKO-AS45-1 (a), U-87 MG (b), and WI-26 VA4 (c) after 24, 48, and 72 hours. Data were normalized to the respective vehicle control values and are presented as the mean ± SEM from nine replicates. *p<0.05, ***p<0.001, ****p<0.0001.

The J. multifida extract was not cytotoxic at any concentration and time points tested in RKO-AS45-1 and WI-26 VA4 cell lines (Fig. 4).

The extract of C. axillare induced a significant reduction in cell survival at the concentration C1 in the RKO-AS45-1 and WI-26 VA4 cell lines at 72 hours (Fig. 5).

In summary, high cytotoxicity of the P. scandens extract was observed at concentration C1 and at all times evaluated for RKO-AS45-1 and U-87 MG within 24 hours. The P. auriculata extract exhibited some cytotoxicity only at concentration C1 and at the 24-hour time point for U-87 MG cell line. The J. gossypiifolia extract was toxic RKO-AS45-1 and to the control cell line, and J. multifida was cytotoxic only to the U-87 MG cell line. C. axillare was cytototoxic to both RKO-AS45-1 and WI-26 VA4 cell lines at concentration C1 within 72 hours of treatment.

Except for P. scandens at concentration C1, the extracts from the other plant species were not able to reduce cell viability to less than 50% in any lineage at the tested concentrations and exposure times. The P. scandens extract showed selective action, preferentially targeting tumor cells over non-tumorigenic human fibroblasts (Table 1).

Figure 4
Cytotoxic effect of Jatropha multifida extract in the cell lines RKO-AS45-1 (a), U-87 MG (b), and WI-26 VA4 (c) after 24, 48, and 72 hours. Data were normalized to the respective vehicle control values and are presented as the mean ± SEM from nine replicates.

Figure 5
Cytotoxic effect of Cestrum axillare extract in the cell lines RKO-AS45-1 (a), U-87 MG (b), and WI-26 VA4 (c) after 24, 48, and 72 hours. Data were normalized to the respective vehicle control values and are presented as the mean ± SEM from nine replicates. *p<0.05.

DISCUSSION

In the present study, the cytotoxic activities of hydroalcoholic extracts of C. axillare, J. gossypiifolia, J. multifida, P. auriculata, and P. scandens were evaluated in colorectal carcinoma (RKO-AS45-1), glioblastoma (U-87 MG), and non-tumorigenic lung fibroblast (WI-26 VA4) cell lines.

Among the extracts tested, only P. scandens demonstrated cytotoxicity, reducing cell survival by 50% at the C1 concentration in RKO-AS45-1, U-87 MG and WI-26 VA4. This plant species contains a naphthoquinone named plumbagin, which is known to have several pharmacological activities (Thakor and Janathia, 2022). Plumbagin showed high cytotoxic activity in endometrial carcinoma (Zhang et al., 2021), esophageal squamous cell carcinoma (KYSE150 and KYSE450) (Cao et al., 2018), cervical carcinoma (HeLa), colon cancer (LoVo) (Shu et al., 2023), EBV-transformed B leukemia (Raji), lung carcinoma (Calu-1), transformed epithelial (Wish) cell lines (Lin et al., 2003), human breast cancer (MCF-7) (De et al., 2019), and glioma cell lines (U251, U87, C6, and GL261) (Zhan et al., 2022). Zhan et al. (2022) showed that plumbagin inhibited in vitro and in vivo glioma cell line growth via targeting NQO1/GPX4-mediated ferroptosis. These authors suggest that plumbagin has the potential to be developed as a novel ferroptosis inducer for cancer treatment or an anti-glioma candidate (Zhan et al., 2022). Ferroptosis is an iron-dependent form of non-apoptotic regulated cell death (RCD) caused by excessive lipid peroxidation, resulting in a ruptured plasma membrane (Lee et al., 2021; Gao et al., 2022). The iron accumulated is the typical hallmark distinguishing ferroptosis from other regulated cell death (e.g., apoptosis, necroptosis, pyroptosis, and autophagy) (Gao et al., 2022; Wang et al., 2022).

On the other hand, the P. auriculata extract exhibited cytotoxicity only for U-87 MG cell lines in 24h. This lower cytotoxicity observed in the present study can be attributed to the low concentration of plumbagin compared to P. scandens. Although the roots of P. auriculata present significant amounts of plumbagin, this substance was either not detected in the leaves (Galal et al., 2013; Teixeira et al., 2024) or found in low concentrations (Mallavadhani et al., 2002).

The C. axillare extract C1 showed cytotoxic activity towards colorectal carcinoma (RKO-AS45-1) and non-tumorous lung epithelium (WI-26 VA4) cell lines in 72h treatment. Earlier studies showed that spirostanol glucosides isolated from C. axillare showed cytotoxic effects on promyelocytic leukemia (HL-60), glioma (SF-295) (Ribeiro et al., 2016a, 2016b), colorectal adenocarcinoma (HCT-116), and ovarian carcinoma (OVCAR-8) (Ribeiro et al., 2016b) cell lines. However, the pharmacological activities of this plant must be better studied.

J. gossypiifolia and J. multifida contain diterpenes and diterpenoids with recognized antineoplastic activities (Taylor et al., 1983; Asep et al., 2017; Zhu et al., 2017; Zhang et al., 2018a, 2018b; Wu et al., 2019; Shari et al., 2023). In the present study, J. gossypiifolia extract C1 was cytotoxic to non-tumor lung epithelial cells and colorectal carcinoma. A similar result was reported with J. gossypiifolia hydroethanol extract, which showed low cytotoxic activity in the human hepatoma HepG2 cell line (Caballero-Gallardo et al., 2023). Diterpenes and diterpenoids were likely present at low levels in the plant extracts.

CONCLUSIONS

P. scandens showed the most significant cytotoxic activities from the five plant species studied, revealing it to be a promising species for future studies aiming to develop new drugs for cancer treatment. Moreover, it exhibits selective action, preferentially targeting tumor cells over non-tumorigenic human fibroblasts. Our results corroborate the literature data regarding the promising antineoplastic activity of P. scandens, probably due to the naphthoquinone plumbagin. Further research into isolated compounds and the development of therapeutic strategies is in progress in our group.

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Publication Dates

• Publication in this collection
  27 Oct 2025
• Date of issue
  Sep-Oct 2025

History

• Received
  18 Oct 2024
• Accepted
  05 Feb 2025