RESUMEN
Plant-based combination strategies have been widely considered in cancer therapy to attenuate chemotherapeutics side effects. The anti-leukemic effect of the whole ginger extract was previously portrayed by our team, and the current study is centered around the cytotoxicity and mechanism of action of a phenolic subsidiary of ginger, GingerenoneA, on pediatric acute lymphoblastic leukemia. GingernoneA imposed, dose-dependently, inhibitory effects on the viability of T and B leukemia cell lines confirmed by MTT assays. Resistance to Dexamethasone, a mostly used chemotherapeutic in acute lymphoblastic leukemia treatments, was overcome by GingernoneA. A synergistic effect of Dexamethasone and GingrenoneA on T leukemia cell lines and patient primary cells was confirmed. Annexin-V/PI and acridine orange/ethidium bromide staining illustrated dose-dependent apoptosis in CCRF-CEM cells developed by GingerenoneA. The intrinsic and extrinsic apoptosis induction and antiproliferative attribution of GingerenoneA were validated by western blot and qPCR. Despite the supposed loss of function in CCRF-CEM cells, TP53 showed increased expression levels and functional activity upon treatment with GingernoneA. Bioinformatic studies revealed the conceivable impact of GingerenoneA on the reactivity of mutant P53 through its binding to Cys124. Our findings may provide novel strategies for therapeutic intervention to ameliorate pALL outcomes.
RESUMEN
P-glycoprotein (P-gp), which was first identified in cancer cells, is an ATP-dependent efflux transporter that expels a wide variety of cytotoxic compounds out of cells. This transporter can decrease the bioavailability of therapeutic drugs by preventing their sufficient intracellular accumulation. Over expression of P-gp in cancer cells lead to multidrug resistance (MDR) phenotype that is one of the main reasons for the failure of chemotherapy. Hence, P-gp inhibition is a favorable method to reverse MDR. In this study, the lignanamides from Cannabis sativa were docked against P-gp to recognize potential binding affinities of these phytochemicals. Tariquidar and zosuquidar, two well-known P-gp inhibitors, were selected as the control ligands. It was observed that cannabisin M and cannabisin N exhibited higher binding affinities (- 10.2 kcal/mol) to drug-binding pocket of P-gp when compared with tariquidar and zosuquidar that showed binding affinities of - 10.1 and - 9.6 kcal/mol, respectively. Based on these findings, cannabisin M and cannabisin N could be good drug candidates against P-gp.
