Panina Svetlana B, Pei Jingqi, Baran Natalia, Konopleva Marina, Kirienko Natalia V
Department of BioSciences, Rice University, Houston, TX, United States.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Front Oncol. 2020 Apr 3;10:435. doi: 10.3389/fonc.2020.00435. eCollection 2020.
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 -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 -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.
急性髓系白血病（AML）是一组侵袭性癌症，死亡率高且复发风险大。目前的治疗方法并不充分，需要新的疗法。最近的发现表明，AML可能对靶向线粒体的化疗药物特别敏感。为了进一步研究这种敏感性，将六种靶向线粒体的化合物[IACS-010759、鱼藤酮、阿糖胞苷、依托泊苷、ABT-199（维奈托克）和羰基氰化物-氯苯腙]分别与六种具有其他活性的化合物配对，包括酪氨酸激酶抑制剂（米哚妥林和达沙替尼）、糖酵解抑制剂（2-脱氧-D-葡萄糖、3-溴丙酮酸和氯尼达明）以及微管稳定剂长春瑞滨。对由此产生的36种药物组合进行了针对MOLM-13和OCI-AML2 AML细胞系的协同细胞毒性测试。四种组合（IACS-010759与长春瑞滨、鱼藤酮与2-脱氧-D-葡萄糖、羰基氰化物-氯苯腙与达沙替尼、维奈托克与氯尼达明）在两种AML细胞系中均显示出协同细胞毒性，并且对肿瘤细胞具有选择性，因为健康外周血单核细胞的存活率显著更高。在这些药物对中，IACS-010759/长春瑞滨最显著地降低了ATP水平并损害了线粒体呼吸和偶联效率。这四种治疗方法中的一些在K-562、KU812（慢性粒细胞白血病）以及CCRF-CEM、MOLT-4（急性淋巴细胞白血病）细胞中也有效，表明这些治疗方法可能对治疗其他形式的白血病有价值。最后，这四种组合中的两种在来自患者样本的原发性AML细胞中保持了高协同性和强选择性，支持了这些治疗方法对患者的潜力。
