Acute myeloid leukemia (AML) is an aggressive group of
cancers with high mortality rates and significant relapse risks. Current treatments are insufficient, and new
therapies are needed. Recent discoveries suggest that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, six compounds that target mitochondria [IACS-010759,
rotenone,
cytarabine,
etoposide,
ABT-199 (
venetoclax), and
carbonyl cyanide m-chlorophenylhydrazone] were each paired with six compounds with other activities, including
tyrosine kinase inhibitors (
midostaurin and
dasatinib), glycolytic inhibitors (2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine), and the microtubule destabilizer
vinorelbine. The 36 resulting
drug combinations were tested for synergistic cytotoxicity against MOLM-13 and OCI-AML2 AML cell lines. Four combinations (IACS-010759 with
vinorelbine,
rotenone with
2-deoxy-D-glucose,
carbonyl cyanide m-chlorophenylhydrazone with
dasatinib, and
venetoclax with
lonidamine) showed synergistic cytotoxicity in both AML cell lines and were selective for
tumor cells, as survival of healthy PBMCs was dramatically higher. Among these drug pairs, IACS-010759/
vinorelbine decreased
ATP level and impaired mitochondrial respiration and coupling efficiency most profoundly. Some of these four treatments were also effective in K-562, KU812 (
chronic myelogenous leukemia) and CCRF-CEM, MOLT-4 (
acute lymphoblastic leukemia) cells, suggesting that these treatments may have value in treating other forms of
leukemia. Finally, two of the four combinations retained high synergy and strong selectivity in primary AML cells from patient samples, supporting the potential of these treatments for patients.