Pravastatina induz parada no ciclo celular e diminuição na produção de VEGF e bFGF em linhagem de Mieloma Multiplo

O Mieloma Múltiplo é uma neoplasia de linfócitos B da medula óssea, caracterizada por inflamação com uma intensa secreção de fatores de crescimento que promovem o aumento do volume do tumor, sobrevivência celular, migração e invasão. O objetivo deste estudo foi avaliar os efeitos da pravastatina, uma droga usada para reduzir o colesterol, em um linhagem de MM. O ciclo celular e viabilidade foram determinadas por Trypan Blue e iodeto de propídio. IL6, VEGF, bFGF e TGF foram quantificadas por ELISA e qRT-PCR, incluindo aqui de HMG CoA redutase. Observou-se a redução da viabilidade das células, aumento de células na fase G0/G1 do ciclo celular e redução no VEGF e bFGF, sem influência na expressão da enzima 3-Metil-Glutaril Coenzima A redutase. Os resultados demonstraram que a pravastatina induz parada no ciclo celular em G0/G1 e diminuição da produção de fatores de crescimento em várias linhas de células de Mieloma.

Palavras-chave:
pravastatina; Mieloma Multiplo; 3-Metil-Glutaril Coenzima A redutase; fator de crescimento do endotélio vascular; fator de crescimento de fibroblasto

Autoria

P. J. J. Trojan

Laboratório Multidisciplinar de Ciências Biológicas e da Saúde, Universidade Estadual de Ponta Grossa – UEPG, Campus de Uvaranas, Av. General Carlos Cavalcanti, 4748, CEP 84030-900, Ponta Grossa, PR, BrazilUniversidade Estadual de Ponta GrossaBrazilPonta Grossa, PR, BrazilLaboratório Multidisciplinar de Ciências Biológicas e da Saúde, Universidade Estadual de Ponta Grossa – UEPG, Campus de Uvaranas, Av. General Carlos Cavalcanti, 4748, CEP 84030-900, Ponta Grossa, PR, Brazil

M. S. Bohatch-Junior

M. F. Otuki

Departamento de Ciências Farmacêuticas, Universidade Estadual de Ponta Grossa – UEPG, Campus de Uvaranas, Av. General Carlos Cavalcanti, 4748, CEP 84030-900, Ponta Grossa, PR, BrazilUniversidade Estadual de Ponta GrossaBrazilPonta Grossa, PR, BrazilDepartamento de Ciências Farmacêuticas, Universidade Estadual de Ponta Grossa – UEPG, Campus de Uvaranas, Av. General Carlos Cavalcanti, 4748, CEP 84030-900, Ponta Grossa, PR, Brazil

F. Souza-Fonseca-Guimarães

Unit Cytokines and Inflammation, Department Infection and Epidemiology Institut Pasteur, 25-28 rue du Docteur Roux, 75015, Paris, FranceDepartment Infection and Epidemiology Institut PasteurFranceParis, FranceUnit Cytokines and Inflammation, Department Infection and Epidemiology Institut Pasteur, 25-28 rue du Docteur Roux, 75015, Paris, France

P. V. Svidnicki

Laboratório de Citogenética e Evolução, Departamento de Biologia Molecular, Estrutural e Genética, Universidade Estadual de Ponta Grossa – UEPG, Campus de Uvaranas, Av. General Carlos Cavalcanti, 4748, CEP 84030-900, Ponta Grossa, PR, BrazilUniversidade Estadual de Ponta GrossaBrazilPonta Grossa, PR, BrazilLaboratório de Citogenética e Evolução, Departamento de Biologia Molecular, Estrutural e Genética, Universidade Estadual de Ponta Grossa – UEPG, Campus de Uvaranas, Av. General Carlos Cavalcanti, 4748, CEP 84030-900, Ponta Grossa, PR, Brazil

V. Nogaroto

D. Fernandes

E. A. Krum

G. M. Favero ^**e-mail: gmfavero@uepg.br

*e-mail: gmfavero@uepg.br

SCIMAGO INSTITUTIONS RANKINGS

Figuras

Figuras (4)

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Figure 1
Pravastatin reduces the number of viable cells in cultured Multiple Myeloma after 72 hours . Cells were cultured in the presence of the pravastatin, or vehicle for 3 days. Three wells of each condition were subjected to the Trypan Blue assay. Data are expressed as mean and standard error of the mean. Statistical analysis was performed using ANOVA followed by Bonferroni´s Multiple Comparison Test. * p < 0.05 compared with the control group.

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Figure 2
Pravastatin induces G0/G1 cell cycle arrest . Flow cytometry Cell cycle analysis, using propidium iodide. (a) Percentage of cell in G0/G1 phase; (b) Percentage of cells in Synthesis Phase; (c) Cells on G2/M Phases. Each bar represents the mean and standard error of the mean of a representative assay performed three times in triplicate. The first bars are 24h, the second 48h and the third bar 72h. (ANOVA followed by Bonferroni´s Multiple Comparison Test).

Thumbnail

Figure 3
Pravastatin induces the loss of VEGF and FGF . Evaluation of different factors in the supernatant culture of MM treated with Pravastatin in different concentrations (ELISA assay). The result shown is representative of 48h of treatment in triplicate. Each bar represents the mean with their standard deviations. Statistical analysis was performed using Student’s t-test. * p < 0.05 compared with the control group.

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Figure 4
Pravastatin not change the expression of HMG CoA reductase . Evaluation of different mRNA by qRT PCR. The result shown is representative of 48h of treatment performed three times in triplicate. Threshold cycle (Ct) was measured and a relative change in the expression level of one specific gene was presented as 2^−ΔΔCt Each bar represents the mean with their standard deviations. Statistical analysis was performed using Student’s t-test. * p < 0.05 compared with the control group.

Figure 1 Pravastatin reduces the number of viable cells in cultured Multiple Myeloma after 72 hours . Cells were cultured in the presence of the pravastatin, or vehicle for 3 days. Three wells of each condition were subjected to the Trypan Blue assay. Data are expressed as mean and standard error of the mean. Statistical analysis was performed using ANOVA followed by Bonferroni´s Multiple Comparison Test. * p < 0.05 compared with the control group.

Figure 2 Pravastatin induces G0/G1 cell cycle arrest . Flow cytometry Cell cycle analysis, using propidium iodide. (a) Percentage of cell in G0/G1 phase; (b) Percentage of cells in Synthesis Phase; (c) Cells on G2/M Phases. Each bar represents the mean and standard error of the mean of a representative assay performed three times in triplicate. The first bars are 24h, the second 48h and the third bar 72h. (ANOVA followed by Bonferroni´s Multiple Comparison Test).

Figure 3 Pravastatin induces the loss of VEGF and FGF . Evaluation of different factors in the supernatant culture of MM treated with Pravastatin in different concentrations (ELISA assay). The result shown is representative of 48h of treatment in triplicate. Each bar represents the mean with their standard deviations. Statistical analysis was performed using Student’s t-test. * p < 0.05 compared with the control group.

Figure 4 Pravastatin not change the expression of HMG CoA reductase . Evaluation of different mRNA by qRT PCR. The result shown is representative of 48h of treatment performed three times in triplicate. Threshold cycle (Ct) was measured and a relative change in the expression level of one specific gene was presented as 2^−ΔΔCt Each bar represents the mean with their standard deviations. Statistical analysis was performed using Student’s t-test. * p < 0.05 compared with the control group.

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Pravastatina induz parada no ciclo celular e diminuição na produção de VEGF e bFGF em linhagem de Mieloma Multiplo

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[1] *e-mail: gmfavero@uepg.br