Chemoprevention COMPOUNDS AND ACTIVITIES curcumin analogs (GVT-0, PGV-0, AND HGV-0): Study of the mechanisms in vitro and in vivo in models of colorectal cancer
ABSTRACT: Chemoprevention of colorectal is the effort to prevent and inhibit the process of colorectal carcinogenesis. The present study aims to determine the chemoprevention activity of curcumin and analogues (GVT-0, PGV-0, and HGV-0) resynthesis results accordance with Rumpel (1954) modification method to the WiDr cell line and colorectal cancer model to Wistar rats. In this study used 125 male Wistar rats were randomly allocated into several groups. Group 1 is the negative control group (DMH 60 mg/kg BW once a week and Na.CMC 0.5% twice a week) for 15 weeks. Groups 2 to 13 are treatment groups, given curcumin, GVT-0, PGV-0, and HGV-0 with respective doses of 20, 40, and 80 mg/kg BW made 2 groups A (DMH, curcumin and its analogues for 15 weeks) and group B (DMH for 15 weeks, curcumin and its analogues continued until 25 weeks), each group consisted of 5 rats. At 26 th week of treatment, all animals sacrificed, colon were fixed in 10% formalin for subsequent observable macroscopic analysis (number of nodules and nodule volume), and microscopic analysis (tumor morphology, expression of APC mutated and COX-2, and proliferation rate) with Haematoxylin and Eosin staining, AgNOR, immunohistochemical staining with anti-COX-2 and anti-APC (rabbit polyclonal anti-COX-2 antibody and rabbit polyclonal antibody anti-APC). Synthesis results show that the purity (in %) of GVT-0, PGV-0, and HGV-0 was 75.08, 89.98, and 100, with the MW 326, 352, and 366 respectively. The results of in vitro studies showed that the respective cytotoxic effect of curcumin, GVT-0, PGV-0, and HGV-0 was 25, 8, 1, and 10 μM with the percentage inhibition of COX-2 against WiDr cells by 25.72, 46.67 and 13.97 for curcumin, PGV-0, and HGV-0. The results of in vivo studies showed that the administration of HGV-0 dose of 40 mg/kg BW for 15 weeks decreases the number and volume of colorectal cancer nodules by 96.1% and 98.8% (P<0.05) against DMH control. Inhibition of mutated APC expression shown in the group given GVT-0 40 mg/kg BW for 15 weeks is about 9.08% and the inhibition of COX-2 expression by HGV-0 40 mg/kg BW for 15 weeks about 47.37%. Giving curcumin and its analogues for 15 weeks can inhibit the proliferation rate of colorectal cancer. Histological features of colorectum supports the results mentioned above as follows: the administration of curcumin and HGV-0 showed complete adenoma, while GVT-0 and PGV-0 still show the incidence of adenomas and adenocarcinomas. The results of this study conclude that the administration of curcumin and analogues (GVT-0, PGV-0, and HGV-0) for 15 weeks effectively decreases the number and volume of colorectal cancer nodules, through the mechanism of inhibition of expression of mutated APC and COX-2, and the rate of proliferation similar to curcumin. Chemoprevention activity of curcumin and analogues was presumably through the inhibition of Wnt signaling and inhibition of the transcription factor NF-ĸB.
