Abstract
RationalCisplatin based cancer therapy is an affordable and effective standard therapy for several solid cancers, including lung, ovarian and head and neck cancers. However, the clinical use of cisplatin is routinely limited by the development of drug resistance and subsequent therapeutic failure. Therefore, methods of circumventing cisplatin resistance have the potential to increase therapeutic efficiency and dramatically increase overall survival. Cisplatin resistance can be mediated by alterations to the DNA damage response, where multiple components of the repair machinery have been described to be client proteins of HSP90. In the present study, we have investigated whether therapy with the novel HSP90 inhibitor onalespib can potentiate the efficacy of cisplatin and potentially reverse cisplatin resistance in ovarian and head and neck cancer cells.MethodsCell viability, cancer cell proliferation and migration capacity were evaluated in vitro on models of ovarian and head and neck cancer cells. Western blotting was used to assess the downregulation of HSP90 client proteins and alterations in downstream signaling proteins after exposure to cisplatin and/or onalespib. Induction of apoptosis and DNA damage response were evaluated in both monotherapy and combination therapy groups.ResultsResults demonstrate that onalespib enhances the efficiency of cisplatin in a dose-dependent manner. Tumor cells treated with both drugs displayed lower viability and a decreased migration rate compared to vehicle-control cells and cells treated with individual compounds. An increase of DNA double strand breaks was observed in both cisplatin and onalespib treated cells. The damage was highest and most persistent in the combination group, delaying the DNA repair machinery. Further, the cisplatin and onalespib co-treated cells had greater apoptotic activity compared to controls.ConclusionThe results of this study demonstrate that the reduced therapeutic efficacy of cisplatin due to drug-resistance could be overcome by combination treatment with onalespib. We speculate that the increased apoptotic signaling, DNA damage as well as the downregulation of HSP90 client proteins are important mechanisms promoting increased sensitivity to cisplatin treatment.
Highlights
Cisplatin (cis-diamminedichloridoplatinum(II), CDDP) is one of the most commonly used antineoplastic drugs worldwide
We have evaluated whether therapy with the novel HSP90 inhibitor onalespib can potentiate the efficacy of cisplatin and reverse cisplatin resistance in vitro
The growth inhibitory effects of monotherapy with cisplatin and the HSP90 inhibitor onalespib were first assessed in ovarian cancer cell lines SKOV3, A2780, and A2780CIS cells as well as head and neck cancer cells (H314) following both 24 h and 72 h drug incubations (Figures 1A,B and Supplementary Figure 1)
Summary
Cisplatin (cis-diamminedichloridoplatinum(II), CDDP) is one of the most commonly used antineoplastic drugs worldwide. The main mechanism of action of cisplatin and other platinum-based analogs involves inter-or intra-strand crosslinks mediated by binding to reactive metal-binding sites on the DNA, primarily the N7 atoms of guanine and adenine in the major groove [2]. These crosslinks disrupt DNA transcription and replication and can result in the induction of cytotoxic processes such as apoptosis. Cisplatin is highly electrophilic and interacts with numerous nucleophilic non-DNA targets in the cytoplasm upon entering the cell These interactions account for additional antineoplastic effects of the drug [2]
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