Oleanolic acid 3-acetate, a minor element of ginsenosides, induces apoptotic cell death in ovarian carcinoma and endometrial carcinoma cells via the involvement of a reactive oxygen species-independent mitochondrial pathway

Hantae Jo; Jeong-Hyun Oh; Dong-Wook Park; Changho Lee; Churl K Min

doi:10.1016/j.jgr.2018.09.003

Oleanolic acid 3-acetate, a minor element of ginsenosides, induces apoptotic cell death in ovarian carcinoma and endometrial carcinoma cells via the involvement of a reactive oxygen species-independent mitochondrial pathway

J Ginseng Res. 2020 Jan;44(1):96-104. doi: 10.1016/j.jgr.2018.09.003. Epub 2018 Sep 19.

Authors

Hantae Jo¹, Jeong-Hyun Oh², Dong-Wook Park³, Changho Lee⁴, Churl K Min¹

Affiliations

¹ Department of Biological Sciences, Ajou University, Suwon, Republic of Korea.
² Oncology Business Unit, MSD-Korea, Seoul, Republic of Korea.
³ Laboratory of Reproductive Medicine, Cheil General Hospital & Women's Healthcare Center, College of Medicine, Dankook University, Seoul, Republic of Korea.
⁴ Department of Pharmacology and Biomedical Science, College of Medicine, Hanyang University, Seoul, Republic of Korea.

Abstract

Objectives: Oleanolic acid, a minor element of ginsenosides, and its derivatives have been shown to have cytotoxicity against some tumor cells. The impact of cytotoxic effect of oleanolic acid 3-acetate on ovarian cancer SKOV3 cells and endometrial cancer HEC-1A cells were examined both in vivo and in vitro to explore the underlying mechanisms.

Methods: Cytotoxic effects of oleanolic acid 3-acetate were assessed by cell viability, phosphatidylserine exposure on the cell surface, mitochondrial release of cytochrome C, nuclear translocation of apoptosis-inducing factor, depolarization of mitochondrial transmembrane potential (ΔΨ_m), and generation of reactive oxygen species (ROS). In vivo inhibition of tumor growth was also assessed with xenografts in immunocompromised mice.

Results: Oleanolic acid 3-acetate exhibited potent cytotoxicity toward SKOV3 and HEC-1A cells by decreasing cell viability in a concentration-dependent manner. Importantly, oleanolic acid 3-acetate effectively suppressed the growth of SKOV3 cell tumor xenografts in immunocompromised mice. Furthermore, oleanolic acid 3-acetate induced apoptotic cell death as revealed by loss of ΔΨ_m, release of cytochrome c, and nuclear translocation of apoptosis-inducing factor with a concomitant activation of many proapoptotic cellular components including poly(ADP-ribose) polymerase, Bcl-2, and caspases-8, caspase-3, and caspase-7. Oleanolic acid 3-acetate, however, caused a decrease in ROS production, suggesting the involvement of an ROS-independent pathway in oleanolic acid 3-acetate-induced apoptosis in SKOV3 and HEC-1A cells.

Conclusion: These findings support the notion that oleanolic acid 3-acetate could be used as a potent anticancer supplementary agent against ovarian and endometrial cancer. Oleanolic acid 3-acetate exerts its proapoptotic effects through a rather unique molecular mechanism that involves an unconventional ROS-independent but mitochondria-mediated pathway.

Keywords: Apoptosis; Endometrial cancer; Oleanolic acids; Ovarian cancer; Reactive oxygen species.