Ckd-581, A Novel Histone Deacetylase Inhibitor, Synergistically Enhances Bortezomib Cytotoxicity In Multiple Myeloma Cells

Abstract For Multiple Myeloma (MM), better anti-MM therapies need to be developed in order to treat refractory, relapsed, and newly diagnosed MM. Recently, Histone deacetylase inhibitors (HDACIs) as a combined drug with bortezomib have been evaluated for the treatment of MM. In this study, we examined to determine the anti-MM effects of a novel HDACI, CKD-581, in MM cells. We treated MM cells with CKD-581 either alone or in combination with Bortezomib. Treatments of 9 different MM cell lines with CKD-581 resulted in dose-and time-dependent growth arrest accompanied by the induction of p21 expression and the reduction of cMYC. CKD-581 enhanced Bortezomib-induced cell growth arrest and apoptosis by further reduction of NF-kB mediated cell signaling pathway, which resulted in functional blockage of ubiquitination-related genes. CKD-581, alone or combined with bortezomib, also abrogated the G2/M cell cycle checkpoint, potentially through the suppression of CHK1 expression as well as synergic growth arrest via induction/reduction of CHKs and cMYC, as revealed in combined treatment of CDK-581 and bortezomib. CKD-581-induced sensitization of Bortezomib resistant MM cells to cytotoxic treatment resulted in an increased number of apoptotic cells as judged by annexin V-positivity and the presence of cleaved caspase-3. In addition, CKD-581 effectively induced the apoptosis of MM cells, which were co-cultured with BMSCs obtained from MM patients' BM. CKD-581 effectively inhibited the secretion of IL-6/sIL-6 and HGF, involved in bone lesion, from MM patients' BMSCs. In animal model, CKD-581 was well tolerated, and resulted in tumor growth inhibition and prolonged survival. In summary, the HDAC inhibitor, CKD-581, is a promising therapeutic agent for MM patients, especially when used in combination with Bortezomib. Citation Format: Chansu Lee, Kwang-Sung Ahn, Woo June Jung, Youngil Koh, Hyo Jung Kim, Hyun Jung Lee, Hwi-Joong Yoon, Sung-Soo Yoon. CKD-581, a novel histone deacetylase inhibitor, synergistically enhances Bortezomib cytotoxicity in multiple myeloma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1695. doi:10.1158/1538-7445.AM2014-1695