Consumption of vitamin B6 reduces colonic damage and protein expression of HSP70 and HO-1, the anti-tumor targets, in rats exposed to 1,2-dimethylhydrazine

Abstract

Abstract. Mounting evidence indicates that vitamin B6 is a protective factor for colon cancer. Elevations in colonic damage, cell proliferation and heat shock proteins (HSPs, molecular chaperones) have been suggested to be associated with colon carcinogenesis. This study was performed to examine the effect of dietary levels of vitamin B6 (1, 7 or 35 mg pyridoxine HCl/kg diet) for 22 weeks on colon damage, epithelial cell proliferation and expression of HSPs in rats exposed to 1,2-dimethylhydrazine (DMH). Supplemental vitamin B6 with a low vitamin B6 diet (1 mg pyridoxine HCl/kg diet) significantly reduced fecal activity of intestinal alkaline phosphatase (an index of intestinal damage) and the colonic epithelium PCNA labeling index (a marker of cell proliferation). Analysis using ELISA indicated that supplemental vitamin B6 significantly lowered protein levels of colonic HSP70 and heme oxygenase-1, HSP32 (HO-1). However, real-time RT-PCR analysis revealed that the mRNA levels of these HSPs were not decreased by supplemental vitamin B6, suggesting that the lowering effect of vitamin B6 on the colon protein expression of the HSPs is mediated by mechanisms not involving altered gene expression. This study provided evidence that dietary supplemental vitamin B6 suppresses colon damage, epithelial cell proliferation and protein expression of HSP70 and HO-1, the targets for anti-tumor agents, in rats exposed to DMH. IntroductionIn previous studies, we provided the first evidence for the anticolon tumor effect of dietary vitamin B6 in azoxymethane (AOM)-treated mice (1,2). In accordance with this finding, accumulating epidemiological evidence indicates an inverse association between vitamin B6 status and colon cancer (3-5). It has been suggested that the anti-tumor effect of vitamin B6 is mediated by lowering cell proliferation, inflammation, angiogenesis, oxidative stress and DNA damage (6-10). However, the underlying mechanism has yet to be clarified.Colon damage and loss of epithelial cells was considered to be a risk factor for colon carcinogenesis (11,12). Epidemiological studies indicated that the association between vitamin B6 status and colon cancer is particularly significant in males consuming alcohol (3). Consumption of alcohol has been reported to cause colonic epithelium damage, which has been considered to promote colon carcinogenesis (13). Evidence suggests that vitamin B6 has a protective role against cytotoxicity in cell culture studies (14,15), although the mechanism remains unclear. Thus, the protective effect of vitamin B6 on colonic damage caused by a carcinogen should be determined.In general, tissue damage caused by stress exposure (heat shock, oxidative stress and hypoxia) is associated with a higher expression of heat shock proteins (HSPs, molecular chaperones) (16-18). HSPs are overexpressed in a variety of human cancers, and are involved in tumor cell proliferation, differentiation, invasion, metastasis, death and recognition by the immune system (16-18). Conversely, HSPs are well known for th...

High concentrations of pyridoxal stimulate the expression of IGFBP1 in HepG2 cells through upregulation of the ERK/c-Jun pathway

“…Consistent with these previous results, the current study observed that dietary vitamin B6 intake, from a supplemental vitamin B6 diet to a low vitamin B6 diet, caused a marked reduction in colon tumorigenesis in mice exposed to azoxymethane (5). Our animal studies suggest that the anti-colon tumor effect of dietary vitamin B6 is partially ascribed to lowering colon cell proliferation, oxidative stress, inflammation and epithelium cell damage (5)(6)(7)(8). Furthermore, we observed that vitamin B6 inhibited lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in mouse macrophage RAW264.7 cells via suppression of nuclear factor-κB (NF-κB) activation (9).…”

Vitamin B6 activates p53 and elevates p21 gene expression in cancer cells and the mouse colon

“…Consistently, increasing epidemiological evidence indicates vitamin B 6 acts as a protective factor against colon cancer (3)(4)(5)(6). We also reported that vitamin B 6 decreases oxidative stress, inflammation, cell proliferation, epithelial cell damage, and angiogenesis, which may lead to lower tumorigenesis (1,2,(7)(8)(9)(10). Moreover, we recently found that high concentrations of pyridoxal (PL) increase the expression of insulin-like growth factor-binding protein 1 (IGFBP1), a putative tumor suppressor, in human hepatoma (HepG2) cells via the upregulation of the ERK/c-Jun pathway (11).…”

Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses

“…A couple of years later, however, the antitumor activity of L-canavanine, a precursor of L-canaline, was shown to be independent of its intracellular conversion into L-canaline, casting doubts on the true relevance of Rosenthal's findings. 71 Later on, the interest on the potential antineoplastic effects provided by vitamin B6 antagonists dropped and most of the preclinical studies on vitamin B6 aimed at testing its potential cytoprotective effects, [72][73][74][75] and hence whether it might be employed to limit the adverse effects of radio-and chemotherapy. 76,77 In 2012, our group has demonstrated that PN synergizes with a large panel of chemotherapeutics (including the DNA-damaging agent cisplatin) as well as several chemotherapy-unrelated stress conditions (for example, hyperthermia, hypoxia, nutrient deprivation, irradiation, inhibition of the respiratory chain and endoplasmic reticulum stress) in the killing of a large panel of cancer cells in vitro.…”