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Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

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....

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Autores principales: Panina, Svetlana B., Pei, Jingqi, Baran, Natalia, Konopleva, Marina, Kirienko, Natalia V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146088/
https://www.ncbi.nlm.nih.gov/pubmed/32318340
http://dx.doi.org/10.3389/fonc.2020.00435
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author Panina, Svetlana B.
Pei, Jingqi
Baran, Natalia
Konopleva, Marina
Kirienko, Natalia V.
author_facet Panina, Svetlana B.
Pei, Jingqi
Baran, Natalia
Konopleva, Marina
Kirienko, Natalia V.
author_sort Panina, Svetlana B.
collection PubMed
description 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.
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spelling pubmed-71460882020-04-21 Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy Panina, Svetlana B. Pei, Jingqi Baran, Natalia Konopleva, Marina Kirienko, Natalia V. Front Oncol Oncology 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. Frontiers Media S.A. 2020-04-03 /pmc/articles/PMC7146088/ /pubmed/32318340 http://dx.doi.org/10.3389/fonc.2020.00435 Text en Copyright © 2020 Panina, Pei, Baran, Konopleva and Kirienko. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Panina, Svetlana B.
Pei, Jingqi
Baran, Natalia
Konopleva, Marina
Kirienko, Natalia V.
Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy
title Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy
title_full Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy
title_fullStr Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy
title_full_unstemmed Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy
title_short Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy
title_sort utilizing synergistic potential of mitochondria-targeting drugs for leukemia therapy
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146088/
https://www.ncbi.nlm.nih.gov/pubmed/32318340
http://dx.doi.org/10.3389/fonc.2020.00435
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