Malformin-A1 (MA1) Sensitizes Chemoresistant Ovarian Cancer Cells to Cisplatin-Induced Apoptosis.

Nada Abdullah,Sergey Dobretsov,Shadia Al Bahlani,Syed Imran Hassan,Jalila Alshekaili,Ikram A Burney,Mahmood Al Kindi,Hamed Al Balushi,Najwa Al Balushi,Yahya Tamimi,Benjamin K Tsang

doi:10.3390/molecules26123624

Abstract

High-grade epithelial ovarian cancer is a fatal disease in women frequently associated with drug resistance and poor outcomes. We previously demonstrated that a marine-derived compound MalforminA1 (MA1) was cytotoxic for the breast cancer cell line MCF-7. In this study, we aimed to examine the effect of MA1 on human ovarian cancer cells. The potential cytotoxicity of MA1was tested on cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CP) ovarian cancer cell lines using AlamarBlue assay, Hoechst dye, flow cytometry, Western blot, and RT-qPCR. MA1 had higher cytotoxic activity on A2780S (IC50 = 0.23 µM) and A2780CP (IC50 = 0.34 µM) cell lines when compared to cisplatin (IC50 = 31.4 µM and 76.9 µM, respectively). Flow cytometry analysis confirmed the cytotoxic effect of MA1. The synergistic effect of the two drugs was obvious, since only 13% of A2780S and 7% of A2780CP cells remained alive after 24 h of treatment with both MA1 and cisplatin. Moreover, we examined the expression of bcl2, p53, caspase3/9 genes at RNA and protein levels using RT-qPCR and Western blot, respectively, to figure out the cell death mechanism induced by MA1. A significant down-regulation in bcl2 and p53 genes was observed in treated cells compared to non-treated cells (p < 0.05), suggesting that MA1 may not follow the canonical pathway to induce apoptosis in ovarian cancer cell lines. MalforminA1 showed promising anticancer activity by inducing cytotoxicity in cisplatin-sensitive and cisplatin-resistant cancer cell lines. Interestingly, a synergistic effect was observed when MA1 was combined with cisplatin, leading to it overcoming its resistance to cisplatin.

Highlights

Ovarian cancer is one of the most common causes of death from cancer amongst women worldwide, and the second most common cause of death from gynecological cancers [1]
The disease becomes resistant to cisplatin, and the 5-year survival rate for High-grade epithelial ovarian cancer (HG-EOC) remains in the region of 15–45% [9]
This study aimed to examine whether MA1 has cytotoxic activity against human ovarian cancer cells, especially in comparison to cisplatin

Summary

Introduction

Ovarian cancer is one of the most common causes of death from cancer amongst women worldwide, and the second most common cause of death from gynecological cancers [1]. High-grade epithelial ovarian cancer (HG-EOC) accounts for 70–80% of all ovarian cancer histological subtypes. The vast majority of patients with HG-EOC are diagnosed with stage III/IV disease [2]. Cisplatin-based chemotherapy with or without anti-angiogenic therapy remains the standard of care [3,4,5]. The vast majority of patients experience a relapse of the disease [6]. A subset of patients with mutations in the BRCA1 or BRCA2 gene responds to inhibitors of the poly (ADP-ribose) polymerase (PARP) enzyme [7,8]. The disease becomes resistant to cisplatin, and the 5-year survival rate for HG-EOC remains in the region of 15–45% [9]. New compounds are urgently needed to achieve better control and overcome the resistance to frontline chemotherapy

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