Combination Treatment With Saha And 5-Azacytidine (Decitabine) Induces Apoptosis And Suppresses Tumor Growth In Preclinical Models Of Chondrosarcoma

Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Several studies have reported that targeting epigenetic mechanisms including DNA methylation or histone acetylation are novel approaches for the treatment of some human cancers. Previous reports have shown that the interaction of DNA methylation and histone modification regulates gene expression. In the present study, we hypothesized that concurrent inhibition of histone acetylation and DNA methylation could result in decreased viability of chondrosarcoma cells both in vitro and in vivo. To test this, we used a panel of chondrosarcoma cell lines including IDH wild type (CH2879), IDH1 mutant (JJ012) and IDH2 mutant (CS1) cell line. Results from our in vitro proliferation assay showed that combination of sub-IC 50 concentrations of the DNA methyltransferase (DNMT) inhibitor Decitabine (5-AZA-dC) and histone deacetylase (HDAC) inhibitor (SAHA) resulted in decreased cell viability of all the three chondrosarcoma cell lines tested when compared to either drug alone. Western blot analysis showed induction of cleaved Poly-ADP Ribose Polymerase (PARP), a known marker of apoptosis. Consistent with augmented DNA damage, combination of Decitabine and SAHA markedly increased the levels of phospho-H2AX, a DNA damage marker, and pro-apoptotic BH3-only proteins such as Bim. Combination treatment also resulted in increased induction of histone acetylation (AcH3) and increased expression of E-Cadherin. Previous reports have shown that E-cadherin is critical for apoptosis and depletion and inhibition of E-Cadherin impairs apoptosis induction via DR4 and DR5 death receptors. To this end, we showed that induction of cleaved PARP by Apo2L/TRAIL stimulation decreased over time when E-Cadherin was knocked down by siRNA. Xenograft studies using IDH2 mutant (CS1) tumor model showed a significant suppression of tumor volume when animals were treated in combination with SAHA and Decitabine compared to single agent treatments. Taken together, our data strongly suggests that combination treatment with SAHA and Decitabine is a novel treatment approach and merits evaluation in the treatment of chondrosarcoma. Citation Format: Tahir Sheikh, Parag Patwardhan, Gary K. Schwartz. Combination treatment with SAHA and 5-Azacytidine (Decitabine) induces apoptosis and suppresses tumor growth in preclinical models of chondrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5066. doi:10.1158/1538-7445.AM2017-5066