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.