TY - JOUR
T1 - Enhanced cytotoxicity of bisantrene when combined with venetoclax, panobinostat, decitabine and olaparib in acute myeloid leukemia cells
AU - Valdez, Benigno C.
AU - Yuan, Bin
AU - Murray, David
AU - Nieto, Yago
AU - Popat, Uday
AU - Andersson, Borje S.
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2022
Y1 - 2022
N2 - 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 γ-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/β-catenin pro-survival pathways were inhibited. These drug combinations may be used in cytoreductive clinical trials for AML patients.
AB - 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 γ-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/β-catenin pro-survival pathways were inhibited. These drug combinations may be used in cytoreductive clinical trials for AML patients.
KW - ABT199
KW - Bisantrene
KW - acute myeloid leukemia
KW - anthracycline
KW - decitabine
KW - olaparib
KW - panobinostat
KW - venetoclax
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U2 - 10.1080/10428194.2022.2042689
DO - 10.1080/10428194.2022.2042689
M3 - Article
C2 - 35188042
AN - SCOPUS:85125439844
SN - 1042-8194
VL - 63
SP - 1634
EP - 1644
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 7
ER -