Toxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500607, Telangana, India; Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, Telangana, India. Electronic address: [Email]
Diarylheptanoids display an array of biological and pharmacological properties. We previously reported the synthesis of a diarylheptanoid Alpinoid c and a series of its derivatives, evaluated their cytotoxicity against various human cancer cells. We found some of these derivatives were significantly more potent than Alpinoid c in preventing the proliferation of various cancer cell lines. Among these, (S, E)-1-(3, 4 dimethoxyphenyl)-6-hydroxy-7-phenylhept-4-en-3-one (DPHP) showed most potent cytotoxicity against COLO205 cells, however, the mechanism by which DPHP prevents the growth of these colon cancer cells remains unknown. In the current study, we investigated the molecular mechanism of DPHP on colon cancer cells. DPHP inhibited the proliferation of COLO205 (IC50 7.01 ± 0.62 μM) and A549 (IC50 20.03 ± 3.11 μM) cells more specifically than normal human colon epithelial cell line NCM460 (IC50 55.6 ± 4.02 μM). In COLO205 cells, DPHP induced cell shrinkage, membrane blebbing, chromatin condensation, phosphatidylserine externalization, and an accumulation of cells at sub-G1 phase. Further analysis these cells treated with DPHP revealed a decrease in mitochondrial membrane potential, an increase in Bax/Bcl2 ratio, the release of cytochrome c, activation of caspases -9, -3/7, and cleavage of the poly-ADP-ribose polymerase. DPHP treatment resulted in inhibition of hypoxia induced VEGF downstream signaling pathway in COLO205 cells is concurrent with inhibition of angiogenesis in CAM. Based on these data we suggest that DPHP significantly induced apoptosis possibly via intrinsic mitochondrial apoptosis pathway and inhibited angiogenesis. Our study suggests DPHP could be a therapeutic agent in treating colon cancer.