Enhanced cytotoxicity of bisantrene when combined with venetoclax, panobinostat, decitabine and olaparib in acute myeloid leukemia cells

Bisantrene (Bis), a topoisomerase-II inhibitor, is less cardiotoxic than the current anthracyclines. Its synergistic cytotoxicity with newly developed antineoplastic drugs has not been reported. We demonstrated the synergism of [Bis + ABT199/venetoclax] in combination with panobinostat (Pano), decitabine (DAC), or olaparib (Ola), known inhibitors of BCL2, histone deacetylase, DNA methyltransferase, and poly(ADP-ribose) polymerase, respectively, in AML cells. [Bis + ABT199] with Pano, DAC, or Ola synergistically inhibited cell proliferation with combination indices of 0.25-0.6, 0.2-0.35, and 0.2-0.4 (at 50% inhibition of proliferation), respectively. Increased gamma-H2AX suggests enhanced DNA damage; cleavages of Caspase 3 and PARP1, DNA fragmentation, increased ROS, and decreased MMP indicate potent apoptosis activation. Similar results were observed using mononuclear cells from leukemia patients but not from healthy donors. The SAPK/JNK signaling pathway was strongly activated by the combination treatments, whereas the PI3K/mTOR and Wnt/beta-catenin pro-survival pathways were inhibited. These drug combinations may be used in cytoreductive clinical trials for AML patients.