teroxirone and Carcinoma--Non-Small-Cell-Lung

Therapy by targeting cancer stem cells (CSCs) is an eligible method to eradicate malignant human tumors. A synthetic triepoxide derivative, teroxirone, was reported effective against the growth of human lung cancer cells by injuring cellular mitochondria functions. And yet it remains unclear if the residual but malicious CSCs can be effectively dissipated following treatment. The current study further affirmed that teroxirone inhibited the propagation of CSCs as enriched from NSCLC cells by inducing p53 that lead to ultimate apoptosis. More evidence supported that the reduced stemness of the spheroids was associated with apoptotic death. The results consolidate the notion that teroxirone is a viable and effective therapeutic agent for eradicating human lung cancer.

Topics: Apoptosis; Biomarkers, Tumor; Bromodeoxyuridine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Fluorescence; Humans; In Situ Nick-End Labeling; Lung Neoplasms; Neoplastic Stem Cells; Spheroids, Cellular; Triazines; Tumor Stem Cell Assay

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