Nedaplatin enhanced apoptotic effects of ABT-737 in human cancer cells via Mcl-1 inhibition

Abstract

Abstract. Platinum compounds, such as cisplatin, carboplatin, oxaliplatin and nedaplatin, are widely used to treat a number of solid malignancies. Nedaplatin is a second-generation platinum complex, based on its pronounced anti-cancer activities against several solid tumors being equivalent to that of cisplatin, but with lower nephrotoxicity. In this context, the present study aimed to investigate the potential anti-cancer effect by combining nedaplatin with ABT-737. It was found that nedaplatin greatly increased ABT-737-mediated apoptosis in A549 and 95-D cells, accompanied by enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3. In addition, this enhancement was also paralleled by cytochrome c release and dissipation of mitochondrial membrane potential. Additional mechanistic investigations revealed that nedaplatin plus ABT-737 exerted a synergistic effect on cancer cells through their ability to accelerate the degradation of Mcl-1. The present study has revealed nedaplatin as a pertinent sensitizer to ABT-737, which opens up new avenues for this promising BH3-mimetic molecule in the clinic. IntroductionNedaplatin, a platinum derivative synthesized to overcome problems of cisplatin resistance, was developed by Shionogi Pharmaceutical Company in 1983 with the aim to provide a treatment with effectiveness similar to cisplatin, but with less nephrotoxicity and gastrointestinal toxicities (1). Nedaplatin produces promising response rates in clinical trials as a monotherapy for the treatment of squamous cell carcinoma of the uterus, cervix, head and neck, ovary, lung and esophagus (2-4). Nedaplatin exerts anti-tumor effects following uptake into tumor cells by binding to DNA bases and inhibiting DNA replication, similar to cisplatin and carboplatin (5). However, the ability of cancer cells to become resistant to nedaplatin remains a notable obstacle to successful chemotherapy; resistance of numerous species of cancer cells to nedaplatin can be reversed by combining with chemotherapeutic agents, including 5-fluorouracil, docetaxel and vindesine (6-8). The identification of new chemotherapy regimens incorporating nedaplatin with other chemotherapeutic agents can enhance the knowledge of nedaplatin resistance and support the development of nedaplatin-based approaches to cancer therapy.The B-cell lymphoma 2 (Bcl-2) family members serve as primary regulators of apoptosis and include both pro-and anti-apoptotic molecules (9). Overexpression of anti-apoptotic Bcl-2 family proteins has been associated with chemotherapy resistance in multiple human cancers (10). Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic protein in the Bcl-2 family, is frequently observed in numerous tumor types and contributes to chemotherapeutic resistance (11).ABT-737 is a small molecule inhibitor of Bcl-2 family proteins. It can bind Bcl-2 and B-cell lymphoma-extra large (Bcl-xL) with high affinity. ABT-737 has shown single agent and combination therapy efficacy against multiple myeloma, acute myeloid leukemia, lymphoma and solid tumor...

Encapsulation of Nedaplatin in Novel PEGylated Liposomes Increases Its Cytotoxicity and Genotoxicity against A549 and U2OS Human Cancer Cells

“…A549 is a non-small cell lung cancer (NSCLC) cell line, the main cancer type nedaplatin is used for treating. A large number of publications have studied the antiproliferative effect of nedaplatin in NSCLC, with a few studies investigating the expression of apoptotic markers and altered cell cycle distribution in response to nedaplatin treatment [ 20 , 26 , 27 , 28 ]. However, genotoxicity or DNA damage induction, assumed to be the main mechanism of action of all platinum drugs, are not assessed in any of these publications and will be addressed in this study.…”

BH3-mimetics: recent developments in cancer therapy

“…Other aspects of drug resistance were also derived from the stress protein Bcl-2-associated athanogene 3 (BAG3), which could stabilize Mcl1 expression, thus contributing to ABT-737 resistance in breast cancer and prostate cells [ 105 ]. Conversely, Mcl1 protein levels were observed to be destabilized when A549 and 95-D cells were treated with Nedaplatin, allowing ABT-737 to induce death with greater efficacy [ 106 ], thus highlighting the effectiveness of Mcl1 co-inhibition in a viable combined therapeutic strategy, and which was confirmed through ARC-mediated transcriptional down-regulation of Mcl1 expression [ 107 ]. Similar ABT-737-enhancing effects have also been reported upon Mcl1 inhibition in retinoblastoma- [ 108 ], melanoma- [ 109 ], breast-, prostate-, colon- [ 110 ] and liver- cancer cells [ 111 ].…”

“…As drug resistance can be mediated by Mcl1 up-regulation in a number of cancer types [ 369 ], which can be sensitized to death upon Mcl1 down-regulation (as in the instance of some ABT-737 co-treatments) [ 99 ], Mcl1 inhibitors are therefore viewed as having better potential for combined chemotherapeutic treatments. Alternative approaches that induce Mcl1 proteasomal degradation (by GDC-094 treatments, for example), have also been effective in overcoming resistance, thus allowing ABT-737 to have greater effects against BC cells [ 346 ] and lung cancer (LC) cells [ 106 ]. Similar effects have also been reported for Mcl1 inhibition and TRAIL co-stimulation of BC cells [ 338 ].…”