The anticancer effects of MPT0G211, a novel HDAC6 inhibitor, combined with chemotherapeutic agents in human acute leukemia cells
Journal
Clinical Epigenetics
Journal Volume
10
Journal Issue
1
Pages
162
Date Issued
2018
Author(s)
Abstract
Background: There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells. Results: MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model. Conclusions: Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia. ? 2018 The Author(s).
Subjects
Acute leukemia; Combination therapy; Histone deacetylase 6; Ku70; Microtubule dynamics
SDGs
Other Subjects
antineoplastic agent; cyclophosphamide; doxorubicin; histone deacetylase 6; mpt 0g211; protein Bax; unclassified drug; vincristine; benzamide derivative; doxorubicin; HDAC6 protein, human; histone deacetylase 6; histone deacetylase inhibitor; vincristine; acute myeloid leukemia; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; Article; cancer combination chemotherapy; cell viability; controlled study; DNA damage response; drug effect; drug efficacy; drug mechanism; drug response; HL-60 cell line; human; human cell; leukemia cell; male; mitochondrion; mitosis; MOLT-4 cell line; mouse; nonhuman; priority journal; protein acetylation; protein expression; T cell leukemia; treatment outcome; tumor growth; tumor volume; tumor xenograft; animal; antagonists and inhibitors; cell cycle; cell proliferation; cell survival; drug potentiation; drug screening; metabolism; tumor cell line; Animals; Benzamides; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Drug Synergism; Histone Deacetylase 6; Histone Deacetylase Inhibitors; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Mice; Vincristine; Xenograft Model Antitumor Assays
Type
journal article