Mechanisms of abemaciclib, a CDK4/6 inhibitor, induced apoptotic cell death in prostate cancer cells in vitro

Gamze Guney Eskiler; Asuman Deveci Ozkan; Ayten Haciefendi; Cemil Bilir

doi:10.1016/j.tranon.2021.101243

Mechanisms of abemaciclib, a CDK4/6 inhibitor, induced apoptotic cell death in prostate cancer cells in vitro

Transl Oncol. 2022 Jan;15(1):101243. doi: 10.1016/j.tranon.2021.101243. Epub 2021 Oct 11.

Authors

Gamze Guney Eskiler¹, Asuman Deveci Ozkan², Ayten Haciefendi³, Cemil Bilir⁴

Affiliations

¹ Department of Medical Biology, Faculty of Medicine, Sakarya University, Korucuk Campus, Sakarya 54290, Turkey. Electronic address: gamzeguney@sakarya.edu.tr.
² Department of Medical Biology, Faculty of Medicine, Sakarya University, Korucuk Campus, Sakarya 54290, Turkey.
³ Department of Medical Biology, Institute of Health Sciences, Sakarya University, Sakarya, Turkey.
⁴ Department of Medical Oncology, Faculty of Medicine, Istinye University VMMedical Park Pendik Hospital, Istanbul, Turkey.

Abstract

The therapeutic effects of abemaciclib (ABE), an inhibitor of cyclin- dependent kinases (CDK) 4/6, on the proliferation of two types of prostate cancer (PC) cells were revealed. In this study, in vitro cytotoxic and apoptotic effects of ABE on metastatic castration-resistant prostate cancer (mCRPC) androgen receptor (AR) negative PC-3 and AR mutant LNCaP PC cells were analyzed with WST-1, Annexin V, cell cycle, reactive oxygen species (ROS), mitochondrial membrane potential, RT-PCR, western blot, and apoptosis protein array. ABE considerably inhibited the growth of PC cells in a dose-dependent manner (p<0.01) and caused significant apoptotic cell death through the suppression of CDK4/6-Cyclin D complex, ROS generation and depolarization of mitochondria membrane potential. However, PC-3 cells were more sensitive to ABE than LNCaP cells. Furthermore, the expression levels of several pro-apoptotic and cell cycle regulatory proteins were upregulated by ABE in especially PC-3 cells with the downregulation of apoptotic inhibitor proteins. Our results suggest that ABE inhibits PC cell growth and promotes apoptosis and thus ABE treatment may be a promising treatment strategy in especially mCRPC. Further preclinical and clinical studies should be performed to clarify the clinical use of ABE for the treatment of PC.

Keywords: Abemaciclib; Apoptosis; CDK4/6; Prostate cancer.