Modulation of Apoptosis and Cell Cycle by Synthetic Bile Acid Derivatives / 대한해부학회지

ABSTRACT

This paper outlines the current understanding of cell cycle modulation and induction of apoptosis in cancer cells by natural and synthetic bile acid. Bile acid homeostasis is tightly regulated in health, and the cellular and tissue concentrations of bile are restricted. However, when pathophysiological processes impair biliary secretion, hepatocytes are exposed to an elevated concentration of bile acids, which triggers cell death. In this context, we have synthesized several new bile acid derivatives. These synthetic bile acids modulate the cell cycle and induce apoptosis in several human cancer cells similar to the effects of natural bile acids. In human breast and prostate cancer cells with different tumor suppressor p53 status, synthetic bile acid induced growth inhibition and apoptosis, and these changes were associated with upregulation of Bax and p21WAF1/CIP1 through a p53-independent pathway. In Jurkat human T cell leukemia cells, the synthetic bile acids induced apoptosis through caspase activation. The synthetic bile acids induced apoptosis in a JNK-dependent manner in SiHa human cervical cancer cells through the induction of Bax and activation of caspases in PC3 prostate cancer cells and induction of G1 phase arrest of the cell cycle in HT29 colon cancer cells. The synthetic bile acids also induced apoptosis in four human glioblastoma multiform cell lines (e.g., U-118MG, U-87MG, T98G, and U-373MG) and one human TE671 medulloblastoma cell line. A chenodeoxycholic acid derivative, called HS-1200, significantly decreased the growth of TE671 medulloblastoma tumor size and increased lifespan in nonobese diabetic and severe combined immunodeficient (NOD/SCID) mice. These findings suggest that these new synthetic bile acids, which are novel apoptosis mediators, might be applicable to the treatment of various human cancer cells.