Novel mechanisms involving chemically modified tetracycline 3 cytotoxicity
Chemically modified tetracycline 3 (CMT-3) is a potential anticancer drug because of its retained matrix metalloproteinases inhibitory property. In the present study, we showed that CMT-3 significantly inhibited the growth and proliferation of human hepatocellular carcinoma HepG(2) cells. Novel mechanisms including increased intracellular autophagy level and high-mobility group box 1 (HMGB1) release were involved. In addition, a major Danshen ingredient, tanshinone IIA sodium sulfonate (TSN-SS), significantly increased the cytotoxic effects of CMT-3 in HepG2 cells. Combining CMT-3 with TSN-SS led to enhanced accumulation of endogenous LC3-II, but reduced HMGB1 cytoplasmic translocation. Altogether, these findings suggest that autophagy and HMGB1 release may play important roles in the anticancer effect of CMT-3. As a novel candidate for cancer therapy, CMT-3 may be used in combination with TSN-SS, which possibly facilitates the execution of a death signal (e. g. autophagy) and prevents the survival of an inducer (e. g. HMGB1 cytoplasmic translocation), thus improving its therapeutic effect. (C) 2014 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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