The hydrolyzed products of iridoid glycoside with β-glucosidase treatment exert anti-proliferative effects through suppression of STAT3 activation and STAT3-regulated gene products in several human cancer cells.

Abstract

CONTEXT:

Iridoids belong to a group of monoterpene compounds with cyclopentane ring and found as mostly the glycoside forms in nature. They act primarily as the defense substances and found in various medicinal plants.

OBJECTIVE:

Although many iridoids exhibit anti-inflammatory and anticancer activities, their molecular targets/pathways are not fully understood. Here, the antiproliferative effect of the hydrolyzed-iridoid product (H-iridoid) form through the STAT3 signaling pathways on tumor cells was investigated.

MATERIALS AND METHODS:

H-iridoids were obtained from five iridoid glycosides with β-glucosidase treatment. The effects of several H-iridoids on cell viability and cell proliferation in tumor cells were measured by the MTT assay. The phosphorylation levels of STAT3, its regulatory molecules, and apoptosis by H-geniposide treatment in DU145 cells were investigated by immunoblots and flow cytometry.

RESULTS:

No single iridoid glycoside exerted any cytotoxicity in the tumor cells, whereas H-iridoids had significant cytotoxic, antiproliferative, and STAT3 inhibitory effects and revealed different potencies depending on their chemical structures. Among the H-iridoids tested, H-geniposide inhibited constitutive STAT3 activation through inhibiting upstream JAK1 and c-Src. Consistent with STAT3 inactivation, H-geniposide downregulated the expressions of Bcl-2, Bcl-xL, survivin, and cyclin D1; this correlated with the accumulation of cells in the sub-G1 phase of the cell cycle and the induction of apoptosis.

DISCUSSION AND CONCLUSIONS:

Our results indicate that the hydrolysis of the glycosidic bond from iridoid glycoside is required for exhibiting cytotoxicity in tumor cells. H-geniposide is the most potent agent and a novel blocker of STAT3 activation in DU145 cells.

• Authors: Hyundu Hwang, Chulwon Kim, Sung-Moo Kim, Wan-Seok Kim, Seung-Hoon Choi, Il-Moo Chang, Kwang Seok Ahn
• Journal: Pharmaceutical biology (Pharm Biol) Vol. 50 Issue 1 Pg. 8-17 (Jan 2012) ISSN: 1744-5116 [Electronic] England
• PMID: 22149883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Iridoid Glycosides
• Iridoids
• STAT3 Transcription Factor
• STAT3 protein, human
• geniposide

Topics

• Antineoplastic Agents, Phytogenic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Flow Cytometry
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydrolysis
• Iridoid Glycosides (chemistry, pharmacology)
• Iridoids (chemistry, pharmacology)
• Neoplasms (drug therapy, pathology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)