Chemoprevention by artesunate in a preclinical model of colorectal cancer involves down regulation of β-catenin, suppression of angiogenesis, cellular proliferation and induction of apoptosis

摘要

Abstract Use of anti-inflammatory drugs is well known to decrease the risk of colorectal cancer, one of the most common causes of cancer related mortality. In view of anti-inflammatory property of artesunate reported in various experimental models, the present study was carried out to evaluate its efficacy in rat model where colon carcinogenesis was induced by 1, 2 dimethylhydrazine (DMH). A time course study revealed that two injections of DMH given at an interval of one week resulted in appearance of multiple plaque lesions and aberrant crypt foci in the colon with a peak effect occurring at the end of 8 weeks. An efficacy study carried out with daily oral administration of artesunate (50 and 150?mg/kg) and aspirin (60?mg/kg) showed a marked reduction in pre-neoplastic changes with a significant decrease in the number of aberrant crypt foci, crypt multiplicity and restoration of histoarchitecture. Both the drugs down regulated β-catenin signaling, reduced the levels of angiogenic markers like VEGF, MMP-9 and inhibited cellular proliferation. The anti-cancer effect of these drugs was concomitant with the pro-apoptotic effect as revealed by increased DNA fragmentation, TUNEL positivity and Bax/Bcl 2 immunoreactivity. This is the first study to evaluate the inhibitory effect of artesunate on pre-neoplastic changes in colon where its chemopreventive effect was found to be comparable to that of aspirin. Our study strengthens the previous findings and shows that it has a preventive and therapeutic potential in the treatment of colon cancer. Graphical abstract Display Omitted Highlights ? Artesunate shows chemopreventive effect in DMH-induced colon cancer in rat. ? It suppresses both gross and microscopic pre-neoplastic changes in rat colon. ? It inhibits carcinogenesis, angiogenesis and cellular proliferation. ? It increases DNA fragmentation and induces apoptosis. ? Its anti-cancer effect is comparable to that of aspirin.