ABSTRACT
Butyric acid is a physiological component of the colonic environment that possesses anti-inflammatory and antitumor properties, among others. However, little is known regarding its effects following direct application on the colonic surface. This study was conducted to investigate the topical anti-inflammatory effect of calcium butyrate in chemically-induced colitis in rats and to evaluate its antitumor properties in vivo and in vitro. The anti-inflammatory activity of calcium butyrate was evaluated in dinitrobenzene sulfonic acid-induced colitis in rats, following intracolonic instillation for 6 consecutive days and its in vivo antitumor activity was evaluated in F344 rats with the azoxymethane (AOM)-induced aberrant crypt foci (AFC) test, following intracolonic instillation for 4 weeks. The in vitro antiproliferative activity was assessed by incubation for 48 h with the HT29, SW620 and HCT116 intestinal tumour cell lines to evaluate the rate of 3H-thymidine uptake. In dinitrobenzene-induced colitis, the intracolonic instillation of calcium butyrate completely prevented body weight reduction in the animals and counteracted the local noxious effects of the irritant by reducing colon edema (-22.7%, P=0.048) and the area of mucosal damage (-48%, P=0.045). In the AOM-induced AFC test, the intracolonic instillation of calcium butyrate significantly reduced the number of AFC in the entire colon (-22.7%, P<0.05). Calcium butyrate, following incubation with the HT29, SW620 and HCT116 tumour cell lines, induced a significant antiproliferative, dose-dependent effect (P=0.046 to P=0.002) in all three strains, as measured by the reduction in 3H-thymidine uptake. Calcium butyrate directly applied to the mucosa of the rat colon was able to ameliorate colonic inflammation, suggesting a possible beneficial role in the treatment of inflammatory colon diseases. Moreover, calcium butyrate exhibited notable antitumor effects in vivo and in vitro; however, their clinical relevance requires confirmation by additional clinical investigations.
ABSTRACT
In the Western world cancer is the second leading cause of mortality, and prostate carcinoma represents in men the second most important type of cancer-causing death. We have already shown that resveratrol (200 microM) triggers in DU145, an androgen-resistant prostate cancer cell line, a necrotic-like cell death, while propolis ethanolic extract (100 microg/ml) causes an apoptotic-like cell demise. The present research is aimed to better elucidate the molecular mechanisms activated by the two micronutrients. Vinorelbine bitartrate, a drug widely used in prostate cancer therapy, was utilized as a reference drug, because it is known to induce apoptosis. The combined treatments between the micronutrients and vinorelbine have been studied to test a possible vinorelbine dose reduction, avoiding its side effects without altering its cytotoxic action. In this investigation SEM and TEM analyses were performed to examine the morphological modifications induced; our observations confirmed necrotic cell features after treatment with resveratrol, and apoptotic modifications after propolis. We also measured cell cycle progression to study a correlation with p21 and p53, two well-known cell cycle checkpoints. The levels of HSP27 and HSP70, two chaperones also exerting antioxidant/antiapoptotic functions, were been also analyzed. Our data indicate that the two micronutrients modulate cell cycle distribution, increasing p53 levels, without the induced HSPs being able to rescue DU145 from death. The results presented suggest chemotherapy based on resveratrol and propolis, alone or in combination with vinorelbine, as a potential useful tool for prostate cancer therapy; the increase in cell cycle control and the modulation of HSPs expression reinforce this suggestion.
