Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells.

Yuko Nakayama,Tomohiro Omura,Tetsuya Minegaki,Ikuko Yano,Kazuhiro Yamamoto,Kohji Takara

doi:10.21873/anticanres.15228

Abstract

Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs. Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells. HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax. HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.

Highlights

Venetoclax is a first-in-class, oral, selective inhibitor of BCL2 apoptosis regulator (BCL2) that is approved worldwide [1, 2]
Venetoclax-resistant cells were newly established through the continuous exposure of HL60 cells, a leukemia cell model, to 1 μM venetoclax; these cells were designated as HL60/VEN cells
The induction of apoptosis by venetoclax was lower in HL60/VEN cells than HL60 cells based on annexin V staining and DNA fragmentation assay (Figure 1B-D)

Summary

Introduction

Venetoclax is a first-in-class, oral, selective inhibitor of BCL2 apoptosis regulator (BCL2) that is approved worldwide [1, 2]. BCL2 an anti-apoptotic protein is a regulator of cell death (i.e., apoptosis) [8]. Evasion of apoptosis is one of the typical characteristics of cancer cells, and a change in expression of BCL2 family proteins has been reported in many cancer types [9,10,11]. Current interest is focused on targeting BCL2 to treat various hematological malignancies, which are typically mediated by the intrinsic regulation of apoptosis or dysregulation of the mitochondrial pathway [12,13,14]. Tumor cells have been found to acquire resistance to cytotoxic anticancer drugs, and to molecular targeting agents. The sensitivity to venetoclax and other anticancer drugs and the molecular changes in HL60/VEN cells were examined and compared with those in HL60 cells

Methods

Results

Conclusion