3 Beta-hydroxyolean-12-en-27-oic acid: a cytotoxic, apoptosis-inducing natural drug against COLO-205 cancer cells.
3Beta-hydroxyolean-12-en-27-oic acid (1), a biologically active, pentacyclic triterpenoid isolated from the rhizomes of Astilbe chinensis, was found to be considerably more cytotoxic toward human colorectal carcinoma (COLO-205) and human cervical squamous carcinoma (HeLa) cells than its congener oleanolic acid (4). This suggests that the position of the COOH group significantly affects the cytotoxicity of oleanane-type pentacyclic triterpene carboxylic acids. To elucidate the underlying biological mechanism responsible for the cytotoxicity of 1, we investigated its growth-inhibitory effect on COLO-205 cells. Compound 1 induced a marked concentration- and time-dependent inhibition of cell proliferation, with the typical morphological characteristics of apoptosis, and under formation of DNA ladders in agarose-gel electrophoresis. Flow-cytometric analysis showed that the cell cycle of COLO-205 cells exposed to 1 was arrested in the G0/G1 phase. Also, 1 increased and decreased the expression of Bax and Bcl-2 proteins, respectively, and lowered the mitochondrial transmembrane potential (delta psi(m)). The peptidic caspase-3 inhibitor NH2-Asp-Glu-Val-Asp-CHO (at 1 microM) could increase the viability of COLO-205 cells previously treated with 1. These results indicate that 1 induces efficient cell apoptosis through down-regulating Bcl-2 expression, up-regulating Bax expression, lowering delta psi(m), and by activating the caspase-3 pathway.
Tu
Jue
J
College of Animal Sciences, Zhejiang University, Hangzhou 310029, PR China.
Sun
Hong-Xiang
HX
Ye
Yi-Ping
YP
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003603:Cytotoxins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D009828:Oleanolic Acid / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
D001688:Biological Products; D002264:Carboxylic Acids; D003603:Cytotoxins; D014315:Triterpenes; D009828:Oleanolic Acid