Abstract
BackgroundThere 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.ResultsMPT0G211 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.ConclusionsCollectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia.
Highlights
There are some limitations of standard chemotherapy for acute leukemia
MPT0G211 induces apoptosis in acute leukemia cells In our previous study, we showed that MPT0G211 is a selective HDAC6 inhibitor with more potent activity than the currently available HDAC6 inhibitor ACY-1215 [20]
We examined the inhibitory effects of MPT0G211 on HDAC6 activity in acute leukemia cells
Summary
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. 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. Leukemia is a hematologic malignancy caused by the rapid proliferation of abnormal blood cells This disease may be acute or chronic. Acute myeloid leukemia (AML) involves the abnormal proliferation of immature myeloid progenitors (e.g., granulocytes, monocytes, red blood cells, and platelets). Both subtypes can progress quickly but differ considerably in terms of survival (5 year survival: 67.5% and 25.9% for ALL and AML, respectively) [2]
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