SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells

Abstract

Limited treatment options are available for chronic myelogenous leukemia (CML) patients who develop imatinib mesylate (IM) resistance. Here we proposed a novel combination regimen, a co-administration of S116836, a novel small molecule multi-targeted tyrosine kinase inhibitor that was synthesized by rational design, and histone deacetylases inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA), to overcome IM resistance in CML. S116836 at low concentrations used in the present study mildly downregulates auto-tyrosine phosphorylation of Bcr-Abl. SAHA, an FDA-approved HDACi drug, at 1 μM has modest anti-tumor activity in treating CML. However, we found a synergistic interaction between SAHA and S116836 in Bcr-Abl-positive CML cells that were sensitive or resistant to IM. Exposure of KBM5 and KBM5-T315I cells to minimal or non-toxic concentrations of SAHA and S116836 synergistically reduced cell viability and induced cell death. Co-treatment with SAHA and S116838 repressed the expressions of anti-apoptosis proteins, such as Mcl-1 and XIAP, but promoted Bim expression and mitochondrial damage. Of importance, treatment with both drugs significantly reduced cell viability of primary human CML cells, as compared with either agent alone. Taken together, our findings suggest that SAHA exerts synergistically with S116836 at a non-toxic concentration to promote apoptosis in the CML, including those resistant to imatinib or dasatinib.

Role of HDACs in normal and malignant hematopoiesis

“…For example, a phase I study of vorinostat with decitabine-treated R/R AML patients who had mixed lineage leukemia (MLL) demonstrated a 35% composite complete response (CRC) rather than a [115]. Hence, combining HDACis with other chemotherapeutic agents is considered to be an effective way to enhance tumor drug sensitivity by improving the cellular efficacy and toxicity of HDACis to tumor cells [116][117][118][119][120][121][122][123][124][125] (Table 3 and Table 4). To date, the different mechanisms of HDACis combined with chemotherapeutic agents such as topoisomerase inhibitors, platinumbased chemotherapeutics, proteasome inhibitors, tyrosine kinase pathway inhibitors and epigenetic modifiers for advanced or drug-resistant hematological malignancies include (1) acetylating histones and inducing p21-CDK-mediated cell cycle arrest; (2) inducing apoptosis by regulating the expression of pro-and antiapoptotic genes through the intrinsic or extrinsic pathway; (3) inducing DNA damage and oxidative stress; (4) activating BTK (in CLL) or inhibiting ERK (in MM) and AKT (in CML) signaling pathways; and (5) regulating the expression of drug resistance-related molecules, such as downregulating BCR-ABL and upregulating Bim in hematological malignancies and downregulating CD44 in multiple myeloma (MM), NF-κB in ALL, γ-catenin in CML, and BRCA1, CHK1 and RAD51 in AML [126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145].…”

Therapeutic activity of DCC‐2036, a novel tyrosine kinase inhibitor, against triple‐negative breast cancer patient‐derived xenografts by targeting AXL/MET

“…The drug concentration resulting in 50% inhibition of cell growth (IC 50 ) was determined. Combination index (CI) studies with MDA‐MB‐231 cells were performed as previously described …”

“…Combination index (CI) studies with MDA-MB-231 cells were performed as previously described. 26 Colony-formation assay MDA-MB-231 and HS-578T cells (2 × 10 5 /well) plated in 6-well plates were treated with 0 or 3.75 μM DCC-2036 for 48 h; then, the cells were collected, washed with PBS and cultured in DMEM lacking drugs. Fourteen days later, the cells were washed with PBS, fixed in 10% methanol for 15 min, and stained with Giemsa for 20 min.…”

Synergistic effects of the combination of 5-Aza‑CdR and suberoylanilide hydroxamic acid on the anticancer property of pancreatic cancer

“…5-Aza-CdR was first characterized 30 years ago and it functions as a mechanism-dependent suicide inhibitor of DNA methyltransferases, with which genes silenced by hypermethylation can be reactivated (25). SAHA is a pan-HDAC inhibitor, and the antitumor effects of SAHA have been reported in chronic myelogenous leukemia (26), lung (27), pancreatic (28), liver (29), cervical (30), head and neck (31), breast (32) and ovarian cancers (33). Our results showed that 5-Aza-CdR or SAHA could inhibit pancreatic cancer cell proliferation in a dose-and time-dependent manner.…”