Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy.

Svetlana B. Panina,Jingqi Pei,Marina Konopleva,Natalia V. Kirienko,Natalia Baran

doi:10.3389/fonc.2020.00435

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.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies that are characterized by the proliferation of undifferentiated or partially differentiated myelogenous blast cells
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 carbonyl cyanide mchlorophenylhydrazone (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)

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies that are characterized by the proliferation of undifferentiated or partially differentiated myelogenous blast cells. Despite efforts to improve treatment, front-line drug regimens for AML have remained essentially unchanged for 20 years, with the exception of very recent approvals of targeted therapies for a few patient populations (e.g., those with IDH1 or FLT3 mutations). Synergistic Combinations for AML Treatment of doxorubicin, daunorubicin, or idarubicin with cytarabine [1]. This treatment has some success in young adults, elderly patients continue to exhibit poor treatment outcomes due to drug toxicity and/or comorbidities, with fewer than 10% of patients surviving more than 2 years [2]. Relapse is a significant problem in AML, due to a recurring population of leukemic cells that often remain resistant to frontline treatment or have acquired drug resistance [3].

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Conclusion