Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-X<inf>L</inf> dual inhibitor that induces Bax-dependent apoptosis

• Type of Material: Article
• Authors: Weilong Yao, Beijing Friendship Hospital, Capital Medical University; Longchuan Bai, University of Michigan Medical School; Shaomeng Wang, University of Michigan Medical School; Yifan Zha, Ascentage Pharma (Suzhou) Co., Ltd; Shi-Yong Sun, Emory University
• Language: English
• Date: 2022-07-01
• Publisher: Elsevier Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors. Published by Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neo.2022.100798
• Title of Journal or Parent Work: Neoplasia (United States)
• Volume: 29
• Start Page: 100798
• End Page: 100798
• Grant/Funding Information: This study was supported by a research fund from Ascentage Pharma Corp Ltd (to SYS).
• Keywords: Apoptosis; Proto-Oncogene Proteins c-bcl-2; Humans; bcl-X Protein; Mcl-1 apoptosis; Myeloid Cell Leukemia Sequence 1 Protein; bcl-2-Associated X Protein; Colorectal Neoplasms; Colorectal cancer; Antineoplastic Agents; Cell Line, Tumor; Bcl-2; Bcl-X(L), APG-1252-M1 (APG-1252)
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

New treatment options, such as targeted therapies, are urgently needed for the treatment of colorectal cancer (CRC), the third leading cause of cancer-related deaths worldwide. The current study focuses on demonstrating the therapeutic efficacies of APG-1252-M1 (an active form of the prodrug, APG-1252 or pelcitoclax), a highly potent Bcl-2/Bcl-XL dual inhibitor in clinical trials, against CRC and understanding the underlying mechanisms. APG-1252-M1 effectively decreased the survival of CRC cell lines, particularly those expressing relatively low levels of Mcl-1, with the induction of apoptosis. High levels of Mcl-1 were significantly correlated with decreased sensitivity of CRC cell lines to APG-1252-M1. When combined with an Mcl-1 inhibitor, APG-1252-M1 synergistically decreased the survival and induced apoptosis of APG-1252-M1-insensitive cell lines with high levels of Mcl-1. This combination further decreased the survival and enhanced apoptosis even in sensitive cell lines with relatively low levels of Mcl-1, whereas enforced expression of ectopic Mcl-1 in these cells abrogated APG-1252-M1’s effects on decreasing cell survival and inducing apoptosis, which could be reversed by Mcl-1 inhibition. APG-1252-M1 rapidly induced cytochrome C and Smac release from mitochondria with caspase-3 and PARP cleavage. Deficiency of Bax in CRC cells abolished APG-1252-M1’s ability to induce apoptosis, indicating that APG-1252-M1 induces Bax-dependent apoptosis. The current study thus demonstrates the potential of APG-1252-M1 as a monotherapy in the treatment of CRC, particularly those with low Mcl-1 expression, or in combination with an Mcl-1 inhibitor, warranting further evaluation in vivo and in the clinic.