RESUMO
ABCG2 is the principal ABC transporter involved in the multidrug resistance of breast cancer. Looking at the current demand in the development of ABCG2 inhibitors for the treatment of multidrug-resistant cancer, we have explored structural requirements of phenyltetrazole derivatives for ABCG2 inhibition by combining classical QSAR, Bayesian classification modelling and molecular docking studies. For classical QSAR, structural descriptors were calculated from the free software tool PaDEL-descriptor. Stepwise multiple linear regression (SMLR) was used for model generation. A statistically significant model was generated and validated with different parameters (For training set: r = 0.825; Q2 = 0.570 and for test set: r = 0.894, r2pred = 0.783). The predicted model was found to satisfy the Golbraikh and Trospha criteria for model acceptability. Bayesian classification modelling was also performed (ROC scores were 0.722 and 0.767 for the training and test sets, respectively). Finally, the binding interactions of phenyltetrazole type inhibitor with the ABCG2 receptor were mapped with the help of molecular docking study. The result of the docking analysis is aligned with the classical QSAR and Bayesian classification studies. The combined modelling study will guide the medicinal chemists to act faster in the drug discovery of ABCG2 inhibitors for the management of resistant breast cancer.
Assuntos
Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Tetrazóis/química , Animais , Teorema de Bayes , Neoplasias da Mama/tratamento farmacológico , Cães , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Modelos Lineares , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Tetrazóis/farmacologiaRESUMO
Multidrug resistance mediated by ATP-binding cassette (ABC) transporters remains a major impediment to cancer chemotherapy. In the present study, we documented that doxorubicin (Dox) or cisplatin-induced prostate cancer (PCa) chemoresistance is predominantly mediated by the induction of ABCG4 in androgen-independent PCa cells. Treatment of DU-145 or PC-3 cells with Dox significantly enhanced the expression of ABCG4 that resulted in the efflux of intracellular Dox. However, incubation of cells with ABCG4 short hairpin RNA resulted in a significant accumulation of Dox and sensitized cells to Dox-induced cytotoxicity. Interestingly, simvastatin synergistically potentiated Dox-induced cytotoxicity by inhibiting ABCG4 in DU-145 and DU-145 Doxres cells. Mechanistically, ABCG4 expression was regulated redox-dependently by intracellular glutathione (GSH) levels. Treatment of cells with N-acetylcysteine or simvastatin restored Dox-induced depletion of GSH levels that in turn inhibited ABCG4 levels. In addition, a reduction in GSH levels by Dox caused a nuclear factor-κB dependent enhancement of c-Myc expression, which led to cAMP-regulatory element-binding protein (CREB) activation. Furthermore, chromatin immunoprecipitation experiments revealed that Dox-induced CREB activation transcriptionally upregulates ABCG4 expression. These results were further confirmed in an in vivo PCa xenograft mice model. Combination of simvastatin and Dox significantly regressed the tumor growth and size with no noticeable Dox-induced cardiotoxic side effects. Intriguingly, DU-145 cells with stably depleted ABCG4 levels not only significantly delayed the development of the tumor but also greatly sensitized the tumor to a low dose of Dox that resulted in complete tumor regression. Collectively, this data reinforces a novel function of ABCG4 in Dox-mediated chemoresistance, and as a potential therapeutic target in drug-induced PCa chemoresistance.