1. Academic Validation
  2. Mcl-1 levels critically impact the sensitivities of human colorectal cancer cells to APG-1252-M1, a novel Bcl-2/Bcl-XL dual inhibitor that induces Bax-dependent apoptosis

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

  • Neoplasia. 2022 Jul;29:100798. doi: 10.1016/j.neo.2022.100798.
Weilong Yao 1 Longchuan Bai 2 Shaomeng Wang 2 Yifan Zhai 3 Shi-Yong Sun 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA 30322, USA.
  • 2 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 3 Ascentage Pharma (Suzhou) Co., Ltd, Suzhou, Jiangsu, PR China.
  • 4 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA 30322, USA. Electronic address: ssun@emory.edu.
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.

Keywords

Bcl-2; Bcl-X(L), APG-1252-M1 (APG-1252); Colorectal cancer; Mcl-1 apoptosis.

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