Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

Abstract

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.

Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy

“…185 Notably, AML cells have associated mutations in mtDNA, reportedly higher mtDNA copy numbers, are dependent on OXPHOS for ATP production (especially in LSCs and IDH-mutated AML cells), and utilize induction of mitochondrial changes to facilitate resistance against treatments. [186][187][188][189][190] These studies both demonstrate AML dependence on mitochondria for survival and persistence and provide context for the need for therapies that target this vulnerability in AML. Here we outline both preclinical and clinical investigations into mitochondrial pathway therapies in AML (Fig.…”

“…It was recently discovered that AML is more susceptible to drugs that target the mitochondria. 187,188 IACS-010759 in combination with microtubule destabilizer, vinorelbine, resulted in synergistic induction of apoptosis in AML cell lines and primary patient samples, while normal peripheral blood mononuclear cells were significantly unaffected. In addition, this drug combination inhibited mitochondrial respiration and lowered mitochondrial ATP levels.…”

Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics

“…Second, another subset of genes encoded proteins that are important for mitochondrial functions, and thereby, probably also for the regulation of cellular metabolism. The targeting of mitochondria or cellular metabolism is now regarded as a possible therapeutic strategy in human AML [ 48 , 49 , 50 , 51 ]. Third, several downregulated genes encoded interacting proteins that are important for the spliceosome or RNA binding/transport.…”

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

“…Currently, there is great interest in developing novel pharmacotherapies that target mitochondrial OXPHOS in leukemia 13,16,17,19,20 . Yet, a large caveat of targeting mitochondria is the ubiquitous necessity of OXPHOS for healthy cellular metabolism.…”

“…In comparison to normal hematopoietic cells, various human leukemias present with increased mitochondrial mass and higher basal respiration rates [10][11][12]15,16 , the latter of which appears to sensitize them to respiratory inhibition 9,13,17,18 . Although these studies have ignited interest in mitochondrialtargeted chemotherapeutics 19,20 , experimental rationale for targeting oxidative phosphorylation (OXPHOS) in leukemia is largely based on the assumption that heightened respiration is representative of the cancerous mitochondrial network's attempt to accommodate an increased ATP demand. However, identical increases in mitochondrial respiration can derive from any number of physiological stimuli, ranging from increased demand for ATP resynthesis to decreased OXPHOS e ciency.…”