Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines

Abstract

Background: Cisplatin (CIS) is widely applied as an anticancer drug for various cancer types, including liver, breast, colorectal, and pancreatic cancers; however, its usage is limited due to side effects. Objective: We investigated whether combined therapy of Graviola (Annona muricata) leaves extract (GLE) and CIS could reduce CIS doses without decreasing its anticancer potential. Methods: The MCF7, HepG2, CaCo2, or PANC1 cells were divided into four groups for each cell line as follows: group1 (G1): untreated cells, G2: cells treated with GLE, G3: cells treated with CIS, and G4: cells treated with GLE, after 2 h treated with CIS. All combinations were prepared as non-constant ratio from GLE. The cytotoxicity, gene expression, cell cycle arrest were determined by MTT assay, real-time PCR, and cell flow cytometry, respectively. Results: Treatment with GLE and/or CIS-induced cytotoxic effect on HepG2, MCF7, CaCo2, and PANC1 cancer cells with the best effect of combined therapy. All twelve non-constant ratio combinations (GLE + CIS) for each cell line resulted in a significant higher cytotoxic effect than single drug treatment. The combination index (CI) values for all combinations were less than one, indicating the presence of synergistic cytotoxic effect between CIS and GLE against the four cancer cell lines. This anticancer effect was triggered through mitochondrial-dependent apoptosis with the downregulation of caspase3, Bax, and p53 and upregulation of Bcl2. GLE also shifted G0/G1 phase of cell cycle arrest induced by CIS to S and G2/M phases. Interestingly, this combined therapy did not affect oxidative stress (indicated by higher malondialdehyde level and lower activities of SOD, CAT, and GPX) induced by CIS; however, it downregulated the expression of MAPK1 and multidrug resistance gene MDR1. Conclusion: These results demonstrate that Graviola leaves extract optimizes the antitumor potential of cisplatin and could be utilized as a natural adjuvant to decrease cisplatin side effects.