Co-Treatment with the Epigenetic Drug, 3-Deazaneplanocin A (DZNep) and Cisplatin after DZNep Priming Enhances the Response to Platinum-Based Therapy in Chondrosarcomas

SIMPLE SUMMARY: Chondrosarcoma is a rare bone tumor characterized by the secretion of a cartilage-like extracellular matrix. Its treatment poses major challenges, since chondrosarcoma is resistant to chemotherapy and radiotherapy. Consequently, chondrosarcoma treatment has been limited over the past 30 years, and consists in the surgical resection of the tumor. Increasing evidence suggests that future cancer therapies will be enhanced by the combination of epigenetic and conventional antitumor agents, leading to further investigations to combine 3-Deazaneplanocin A (DZNep), an epigenetic drug, with existing antitumoral agents. We show by in vitro and in vivo experiments that an optimised DZNep/cisplatin combination reduces chondrosarcoma viability and induces apoptosis more effectively than each of the drugs alone. These results demonstrate the potential use of this epigenetic-chemotherapeutic combination approach for further studies and management of chondrosarcoma treatment. ABSTRACT: Background: We have previously shown that 3-Deazaneplanocin A (DZNep) induces apoptosis in chondrosarcomas. Herein, we tested whether the combination of this epigenetic drug to a standard anticancer therapy may enhance the response to each drug in these bone tumors. Methods: Two chondrosarcoma cell lines (SW1353 and JJ012) were cultured in the presence of DZNep and/or cisplatin. Cell growth was evaluated by counting viable cells, and apoptosis was determined by Apo2.7 expression by flow cytometry. In vivo, the antitumoral effect of the DZNep/cisplatin combination was assessed through measurements of tumor volume of JJ012 xenografts in nude mice. Results: In vitro, the DZNep/cisplatin combination reduced cell survival and increased apoptosis compared to each drug alone in chondrosarcomas, but not in normal cells (chondrocytes). This enhancement of the antitumoral effect of the DZNep/cisplatin combination required a priming incubation with DZNep before the co-treatment with DZNep/cisplatin. Furthermore, in the chondrosarcoma xenograft mice model, the combination of both drugs more strongly reduced tumor growth and induced more apoptosis in tumoral cells than each of the drugs alone. Conclusion: Our results show that DZNep exposure can presensitize chondrosarcoma cells to a standard anticancer drug, emphasizing the promising clinical utilities of epigenetic-chemotherapeutic drug combinations in the future treatment of chondrosarcomas.