cytochrome-c-t and teroxirone

The prevalent human hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality. The small molecular weight triepoxide derivative, 1,3,5-triazine-2,4,6(1H,3H,5H)-tri-one-1,3,5-tri-(oxiranylmethyl) (teroxirone), has been proved effective against the proliferation of lung cancer cells. The purpose is to further examine if teroxirone regulate growth and metastatic potential of HCC cells with aims at disclosing more of the reaction mechanisms.. Measurements of cell viability and flow cytometry were conducted to test sensitivities of teroxirone against HCC cells. The signaling pathway leading to apoptotic death was unraveled by Western blotting analysis. The metastatic progression was evaluated by cell-based phenotype assay that included migration, invasion, gelatin zymography and wound assay. The in vivo drug efficiency was done in immune-deficient mice with the established xenograft tumors.. Teroxirone inhibited growth of HCC cells, but not hepatic cells. The drug induced apoptosis in HCC cells bearing mutant p53. Pretreatment of caspase-3 inhibitor restored cell viabilities by suppressing extrinsic pathway-mediated cell death. More experiments suggested that sub-apoptotic concentrations of teroxirone mitigated migration, invasion and wound healing of HCC cells. The drug reduced growth of the xenograft tumors as established in animal models by activating apoptotic death.. The findings asserted that teroxirone is an eligible addition to the existing options as an anticancer agent to eliminate HCC.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Caspase Inhibitors; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cytochromes c; Female; Humans; Liver Neoplasms; Matrix Metalloproteinases; Mice, Nude; Neoplasm Invasiveness; Signal Transduction; Triazines; Wound Healing; Xenograft Model Antitumor Assays

In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells.

Topics: Animals; Annexin A5; Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Comet Assay; Cytochromes c; DNA Damage; Down-Regulation; Humans; Mice; Mice, Nude; RNA, Small Interfering; Triazines; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays