deoxyelephantopin and Nasopharyngeal-Neoplasms

Isolated from Elephantopus scaber L., a Chinese medicinal herb that is widely used to prevent and treat cancers in China, isodeoxyelephantopin (ESI) exerted antitumor effects on several cancer cells. However, its antitumor mechanism is still not clear. In this study, we found that ESI could induce G2/M arrest and subsequently stimulate cell apoptosis in dose- and time-dependent manners. We used SILAC quantitative proteomics to identify ESI-regulated proteins in cancer cells, and found that 124 proteins were significantly altered in expression. Gene ontology and Ingenuity Pathway Analysis revealed that these proteins were mainly involved in the regulation of oxidative stress and inflammation response. Functional studies demonstrated that ESI induced G2/M arrest and apoptosis by inducing ROS generation, and that antioxidant N-acetyl-l-cysteine could block the ESI-induced antitumor effects. Accumulated ROS resulted in DNA breakage, subsequent G2/M arrest and mitochondrial-mediated apoptosis. ESI upregulated the expression of anticancer inflammation factors IL-12a, IFN-α, and IFN-β through ROS-dependent and independent pathways. The current work reveals that ESI exerts its antitumor effects through ROS-dependent DNA damage, mitochondrial-mediated apoptosis mechanism and antitumor inflammation factor pathway.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Cell Cycle Checkpoints; Cell Line, Tumor; Cytokines; Humans; Lactones; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Protein Interaction Maps; Proteome; Proteomics; Sesquiterpenes

Deoxyelephantopin (ESD), a naturally occurring sesquiterpene lactone present in the Chinese medicinal herb, Elephantopus scaber L. exerted anticancer effects on various cultured cancer cells. However, the cellular mechanisms by which it controls the development of the cancer cells are unavailable, particularly the human nasopharyngeal cancer CNE cells. In this study, we found that ESD inhibited the CNE cell proliferation. Cell cycle arrest in S and G2/M phases was also found. Western blotting analysis showed that modulation of cell cycle regulatory proteins was responsible for the ESD-induced cell cycle arrest. Besides, ESD also triggered apoptosis in CNE cells. Dysfunction in mitochondria was found to be associated with the ESD-induced apoptosis as evidenced by the loss of mitochondrial membrane potential (ΔΨm), the translocation of cytochrome c, and the regulation of Bcl-2 family proteins. Despite the Western blotting analysis showed that both intrinsic and extrinsic apoptotic pathways (cleavage of caspases-3, -7, -8, -9, and -10) were triggered in the ESD-induced apoptosis, additional analysis also showed that the induction of apoptosis could be achieved by the caspase-independent manner. Besides, Akt, ERK and JNK pathways were found to involve in ESD-induced cell death. Overall, our findings provided the first evidence that ESD induced cell cycle arrest, and apoptosis in CNE cells. ESD could be a potential chemotherapeutic agent in the treatment of nasopharyngeal cancer (NPC).

Topics: Antineoplastic Agents; Apoptosis; Asteraceae; Caspases; Cell Cycle; Cell Line, Tumor; Cytochromes c; Humans; Lactones; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-akt; Sesquiterpenes