Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines
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ORIGINAL ARTICLE
Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines Mai G. Awad1 · Ramadan A. Ali1 · Dalia D. Abd El‑Monem1 · Mohammed A. El‑Magd2 Received: 5 March 2020 / Accepted: 17 June 2020 © The Korean Society of Toxicogenomics and Toxicoproteomics 2020 2020
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. Keywords Graviola leaf · Cisplatin · Synergism · Apoptosis · MDR · ROS
Introduction Cisplatin (CIS), also known as cis-Diamminedichloroplatinum (CDDP), is a widely used chemotherapeutic agent against many cancers, including liver, breast, colorectal, and pancreatic cancers (Fuertes et al. 2003). However, similar to most of other chemotherapeutic agents, CIS has no selective effect on cancer cells as it can intermingle * Mohammed A. El‑Magd [email protected] 1
Department of Zoology, Faculty of Women for Art, Science and Education, Ain Shams University, Cairo, Egypt
Department of Anatomy, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr Elsheik, Egypt
2
with DNA of cancer an
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