Inhibitory impacts of chemically modified tetracycline-3 and underlying mechanism in human cervical cancer cells.

Abstract

Chemically modified tetracyclines (CMTs) have been rationally designed from tetracyclines. The CMTs that show the antimicrobial properties are eliminated, whereas matrix metalloproteinase inhibitory properties are retained. Interestingly, CMT-3 (COL-3, by eliminating the dimethylamino, methyl, and hydroxyl functionalities on the basic tetracycline structure), one of the CMTs, has shown strong anticancer activity. In this study, we found that CMT-3 showed dose-dependent and time-dependent cytotoxicity in HeLa and Siha cells, two human cervical cancer cell lines. HeLa cells were more sensitive to CMT-3 compared with Siha cells. The antiproliferation potential of CMT-3 was associated with the mitochondrial apoptosis pathway, increasing reactive oxygen species level, and proapoptosis protein (e.g. caspase-3) expression, but decreasing antiapoptosis protein expression (e.g. Bcl-2). N-acetylcysteine (a reactive oxygen species inhibitor) and Z-LEHD-FMK significantly reduced or blocked the apoptosis event resulting from cytotoxic effect of CMT-3. CMT-3 also induced G0/G1 phase arrest with the reduction of cell cycle regulatory protein cyclin E and the translocation of NF-κB from the cytoplasm to the nucleus. Our findings provide the important foundation for further investigation of the underlying mechanism for the anticancer activity of CMT-3 and the potential application of CMT-3 as a new therapeutic candidate for clinical cervical cancer therapy.

• Authors: Lin Zhao, Jiaying Xu, Yang Yang, Yu Chong, Chang Liu, Yang Jiao, Saijun Fan
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 24 Issue 8 Pg. 799-809 (Sep 2013) ISSN: 1473-5741 [Electronic] England
• PMID: 23722439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antioxidants
• Apoptosis Regulatory Proteins
• Caspase Inhibitors
• Cell Cycle Proteins
• Tetracyclines
• tetracycline CMT-3

Topics

• Active Transport, Cell Nucleus
• Antineoplastic Agents (chemistry, pharmacology)
• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Caspase Inhibitors (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Proliferation (drug effects)
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Female
• HeLa Cells
• Humans
• Molecular Structure
• Oxidative Stress (drug effects)
• Structure-Activity Relationship
• Tetracyclines (chemistry, pharmacology)
• Time Factors
• Uterine Cervical Neoplasms (metabolism, pathology)