RESUMO
Multidrug resistance remains a major challenge in the chemotherapy of breast cancer. Guajadial, a natural meroterpenoid, has been found to possess anti-tumor activity. However, the role of guajadial in drug resistance has not been investigated. The aim of this study was to evaluate the effect of guajadial on drug resistance in drug-resistant breast cancer cells. Cell viability was measured by MTT assay, and the IC50 values were calculated. The expression of ATP-binding cassette (ABC) transporters including P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) was detected by qRT-PCR and western blot. The expression of Akt, p-Akt, p70S6K, and p-p70S6K was determined by western blot. We found that guajadial significantly inhibited cell viability of parental non-resistant cell line MCF-7, adriamycin (ADR)-resistant cell line MCF-7/ADR, and paclitaxel (PTX)-resistant cell line MCF-7/PTX in a dose-dependent manner. Guajadial enhanced ADR and PTX sensitivity of MCF-7/ADR and MCF-7/PTX cells, and inhibited the expression of P-gp and BCRP. Guajadial treatment resulted in an inactivation of PI3K/Akt pathway in drug-resistant MCF-7â¯cells. In conclusion, guajadial acted as an inhibitor of drug resistance, which might be mediated by the inhibition of ABC transporter expression and PI3K/Akt pathway in drug-resistant breast cancer cells. These findings suggested that guajadial treatment might be a new approach to overcome the drug resistance in the chemotherapy of breast cancer.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Terpenos/farmacologia , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Humanos , Células MCF-7 , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismoRESUMO
Guajadial, one of natural dialdehyde meroterpenoids, demonstrated significant antineoplasmic activity. The present research was to investigate the inhibitory effects of guajadial by using two NSCLC cells (A549 and H1650) proliferation and migration. Western blotting was employed to explore the underlying mechanisms of VEGF receptor (VEGFR)2-mediated. This research indicated that guajadial not only inhibited endothelial cell proliferation and migration but also suppress tumor growth in human NSCLC xenograft mouse models. It is also suggested that guajadial inhibited A549 proliferation via blocking the Ras/MAPK pathway.