title: 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.affiliation: School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Jiaying
authors.initials: J
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Chong
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.forename: Saijun
authors.initials: S
authors.lastname: Fan
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D013754:Tetracyclines; C117155:tetracycline CMT-3