A mechanism for increased sensitivity of acute myeloid leukemia to mitotoxic drugs

Abstract

Mitochondria play a central and multifunctional role in the progression of tumorigenesis. Although many recent studies have demonstrated correlations between mitochondrial function and genetic makeup or originating tissue, it remains unclear why some cancers are more susceptible to mitocans (anticancer drugs that target mitochondrial function to mediate part or all of their effect). Moreover, fundamental questions of efficacy and mechanism of action in various tumor types stubbornly remain. Here we demonstrate that cancer type is a significant predictor of tumor response to mitocan treatment, and that acute myeloid leukemias (AML) show an increased sensitivity to these drugs. We determined that AML cells display particular defects in mitochondrial metabolism that underlie their sensitivity to mitocan treatment. Furthermore, we demonstrated that combinatorial treatment with a mitocan (CCCP) and a glycolytic inhibitor (2-deoxyglucose) has substantial synergy in AML cells, including primary cells from patients with AML. Our results show that mitocans, either alone or in combination with a glycolytic inhibitor, display anti-leukemia effects in doses much lower than needed to induce toxicity against normal blood cells, indicating that mitochondria may be an effective and selective therapeutic target.

Melittin—A Natural Peptide from Bee Venom Which Induces Apoptosis in Human Leukaemia Cells

“…For this reason, we decided to perform an analysis of the physiological cells which occur in blood flow and can be a healthy control to verify the cytotoxic effect. For this study, we used PMBCs obtained from healthy donors, which are very often used and suggested as a healthy control in leukaemia studies [48,49]. Our result demonstrates that the beneficial effect of melittin, which can act as a potential anti-leukemic agent, does not induce any negative changes (in cell viability and morphology) in PBMCs (Figure 3).…”

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

“…In a previous study, we determined that leukemia cells were significantly more sensitive to mitochondria-targeted drugs than other cancer types (24). In addition, the combination of mitocans with the glycolytic inhibitor 2-deoxy-D-glucose exhibited synergy in killing leukemia cells (24).…”

“…In a previous study, we determined that leukemia cells were significantly more sensitive to mitochondria-targeted drugs than other cancer types (24). In addition, the combination of mitocans with the glycolytic inhibitor 2-deoxy-D-glucose exhibited synergy in killing leukemia cells (24). To explore the potential for mitocan-driven synergetic cell killing, we selected 6 mitocans targeting different mitochondrial functions (OxPhos, mitochondrial membrane potential, mtDNA replication, and apoptosis) and tested their combination with six complementary drugs ( Table S3).…”

“…To explore the potential for mitocan-driven synergetic cell killing, we selected 6 mitocans targeting different mitochondrial functions (OxPhos, mitochondrial membrane potential, mtDNA replication, and apoptosis) and tested their combination with six complementary drugs ( Table S3). Mitocans were selected based on their presence in current chemotherapeutic regimens for AML, such as cytarabine (1) or ABT-199 (34), promising clinical trials for patients with leukemia, such as IACS-010759 (35), etoposide (36), or preliminary and published data, indicating selectivity to AML, such as rotenone and CCCP (24). Complementary drugs included tyrosine-kinase inhibitors [midostaurin (37) and dasatinib (38), both of which are used in leukemia patients], glycolytic inhibitors (2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine), and a microtubule destabilizer [vinorelbine (39)] (Table S3).…”

“…ara-C, cytarabine; CCCP, carbonyl cyanide mchlorophenylhydrazone; DAS, dasatinib; ECAR, extracellular acidification rate; ET, etoposide; ETC, electron transport chain; IACS, IACS-010759; LND, lonidamine; MID, midostaurin; OCR, oxygen consumption rate; OxPhos, oxidative phosphorylation; RT, rotenone; VIN, vinorelbine; 2-DG, 2-deoxy-D-glucose; 3-BP, 3-bromopyruvate. compounds that target mitochondria to disrupt tumor cells (23). Using both bioinformatics and cell culture studies, we recently determined that AML cells are particularly sensitive to mitocans, whether alone or in combination, and exposure to these compounds can effectively kill these cells (24). Interestingly, the drugs used for induction and consolidation (cytarabine and daunorubicin or doxorubicin) both have underappreciated effects on mitochondria (25,26).…”