Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine
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RESEARCH ARTICLE
Open Access
Venetoclax and alvocidib are both cytotoxic to acute myeloid leukemia cells resistant to cytarabine and clofarabine Rie Nishi1*, Hiroko Shigemi2, Eiju Negoro1, Miyuki Okura1, Naoko Hosono1 and Takahiro Yamauchi1
Abstract Background: Cytarabine (ara-C) is the major drug for the treatment of acute myeloid leukemia (AML), but cellular resistance to ara-C is a major obstacle to therapeutic success. The present study examined enhanced anti-apoptosis identified in 3 newly established nucleoside analogue-resistant leukemic cell line variants and approaches to overcoming this resistance. Methods: HL-60 human AML cells were used to develop the ara-C– or clofarabine (CAFdA)-resistant variants. The Bcl-2 inhibitor venetoclax and the Mcl-1 inhibitor alvocidib were tested to determine whether they could reverse these cells’ resistance. Results: A 10-fold ara-C-resistant HL-60 variant, a 4-fold CAFdA-resistant HL-60 variant, and a 30-fold CAFdAresistant HL-60 variant were newly established. The variants demonstrated reduced deoxycytidine kinase and deoxyguanosine kinase expression, but intact expression of surface transporters (hENT1, hENT2, hCNT3). The variants exhibited lower expression of intracellular nucleoside analogue triphosphates compared with non-variant HL-60 cells. The variants also overexpressed Bcl-2 and Mcl-1. Venetoclax as a single agent was not cytotoxic to the resistant variants. Nevertheless, venetoclax with nucleoside analogs demonstrated synergistic cytotoxicity against the variants. Alvocidib as a single agent was cytotoxic to the cells. However, alvocidib induced G1 arrest and suppressed the cytotoxicity of the co-administered nucleoside analogs. Conclusions: Three new nucleoside analogue-resistant HL-60 cell variants exhibited reduced production of intracellular analogue triphosphates and enhanced Bcl-2 and Mcl-1 expressions. Venetoclax combined with nucleoside analogs showed synergistic anti-leukemic effects and overcame the drug resistance. Keywords: Venetoclax, Bcl-2, Alvocidib, Mcl-1, Cytarabine (ara-C), Clofarabine (CAFdA)
Background Cytarabine (1-β-D-arabinofuranosylcytosine; ara-C) is the major chemotherapeutic agent for acute myeloid leukemia (AML) [1, 2]. Remission induction chemotherapy consists of regular-dose 7-day administration of ara-C plus 3-day administration of daunorubicin or idarubicin. This * Correspondence: [email protected] 1 Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan Full list of author information is available at the end of the article
regimen has been used for over 30 years as the gold standard [3], providing complete response (CR) rates of nearly 80%, but only 30–40% of patients achieve cure [4, 5]. Because the clinical efficacy of ara-C is not long-lasting, most patients deteriorate and do not respond to further chemotherapy regimens. Reversing the ineffectiveness of anticancer agents is indispensable [1]. Ara-C, a nucleoside analog, is ta
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