ABSTRACT
The formation and metastasis of tumor cells are closely related to the gene regulation. It is critical to elucidate the molecular mechanism of a compound using in cancer therapy. In this article, we reviewed the anti-cancer molecular mechanism of arsenic trioxide and artemisinin. Its anti-cancer function mainly includes:regulation of ① cell cycle regulatory proteins to inhibit tumor cell proliferation, ② cell apoptosis signal transduction pathway to promote apoptosis in tumor cells, ③ immortalization associated genes to reduce the life of tumor cells, ④ angiogenesis/invasion/metastasis gene to block the spread of tumor cells, ⑤ promoter methylation and protein ubiquitination gene to enhance anti-oncogene expression and ubiquitin-mediated protein degradation, ⑥ microRNA to inhibit proliferation or induce apoptosis in tumor cells, ⑦ DNA synthesis and repair of DNA damage and repair gene to decrease the DNA synthesis of tumor cells, ⑧ signal transduction pathways of cell proliferation/apoptosis and invasion/metastasis etc., ⑨ the expression of hor-mone receptors and so on. We indicated the problems existing in current studies and also prospected the future of using the compound to fight cancer.
ABSTRACT
Gambogic acid (GA) is an anticancer agent in phase ‖b clinical trial in China but its mechanism of action has not been fully clarified. The present study was designed to search the possible target-related proteins of GA in cancer cells using proteomic method and establish possible network using bioinformatic analysis. Cytotoxicity and anti-migration effects of GA in MDA-MB-231 cells were checked using MTT assay, flow cytometry, wound migration assay, and chamber migration assay. Possible target-related proteins of GA at early (3 h) and late stage (24 h) of treatment were searched using a proteomic technology, two-dimensional electrophoresis (2-DE). The possible network of GA was established using bioinformatic analysis. The intracellular expression levels of vimentin, keratin 18, and calumenin were determined using Western blotting. GA inhibited cell proliferation and induced cell cycle arrest at G2/M phase and apoptosis in MDA-MB-231 cells. Additionally, GA exhibited anti-migration effects at non-toxic doses. In 2-DE analysis, totally 23 possible GA targeted proteins were found, including those with functions in cytoskeleton and transport, regulation of redox state, metabolism, ubiquitin-proteasome system, transcription and translation, protein transport and modification, and cytokine. Network analysis of these proteins suggested that cytoskeleton-related proteins might play important roles in the effects of GA. Results of Western blotting confirmed the cleavage of vimentin, increase in keratin 18, and decrease in calumenin levels in GA-treated cells. In summary, GA is a multi-target compound and its anti-cancer effects may be based on several target-related proteins such as cytoskeleton-related proteins.