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 HepG2 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 an ovel 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.