PLP has been found to be effective

PLP has been found to be effective inhibitor of many enzymes that have Pefloxacin Mesylate synthesis for phosphate-containing substrates or effectors, including RNA polymerase [14], [15], reverse transcriptase [16], and DNA polymerase [17], [18]. Oka et al. [19], [20] reported that vitamin B6 deficiency generally enhances gene expression in rat liver, including that of glycogen phosphorylase. Recently, they have reported that PLP first binds to Lys197 of HNF1 protein, a tissue-specific transcription factor, and modulates DNA binding activity, which in turn suppresses expression of the albumin gene in rat liver [21]. The possibility that the inhibitory effect of dietary vitamin B6 on colon cell proliferation is mediated through alternations of gene expression remains to be examined.
Oxidative stress It has been reported that c-myc and c-fos expression can be induced by oxidative stress [22], [23]. In vitro study has indicated that vitamin B6 has a strong antioxidative effect [24]. Some animal research demonstrated that vitamin B6 deficiency leads to greater lipid peroxidation in plasma and liver when the animal consumes a high fat diet [25]. Thus, Komatsu et al. [26] postulated that the suppression effect of vitamin B6 on the cell proliferation might be mediated through reduced oxidative stress. As oxidative stress markers, colonic 8-hydroxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) were examined in the AOM-treated mice fed graded levels of vitamin B6. The immunohistochemical analysis showed that supplementation of vitamin B6 to low vitamin B6 diet (1 mg/kg diet) significantly suppressed the levels of 8-OHdG and 4-HNE [26]. The alteration of these oxidative stress markers significantly correlated with the expression of c-myc and c-fos proteins. The concentration of serum lipid peroxide was also higher in the 1 mg pyridoxine HCl/kg diet group than in the other groups [26]. Thus, reduced oxidative stress by vitamin B6 supplementation might be in part involved in the mechanism of its preventive effect on tumorigenesis (Fig. 2).
Nitric oxide Nitric oxide (NO), one of the oxygen free radicals, has been considered to play an important role in the colon carcinogenesis by elevating cyclooxygenase-2 and angiogenesis [27,87]. The expression and activity of inducible NO synthase (iNOS) are higher in human adenomas [29]. Some studies have also demonstrated that AOM-induced colon tumors have increased an expression and/or activity of iNOS when compared to levels in adjacent colonic tissue [30]. The production of NO and the expression of iNOS mRNA is elevated by oxidative stress, which is induced by superoxide [31]. Komatsu et al. [26] have further examined the effect of dietary vitamin B6 on colonic expression of iNOS protein in AOM-treated mice. The result showed a significant depression in the colonic iNOS protein by elevating dietary vitamin B6. The expression of iNOS protein was associated with the levels of 8-OHdG and 4-HNE. Thus, the lower NO production by vitamin B6 might also partially lead to reduced colon tumorigenesis (Fig. 2).
Angiogenesis Some tumor cells recruit new capillary blood vessels, called angiogenesis, that support the growth [32]. Metastases are also dependent on angiogenesis to be shed from a primary tumor and to grow at their target organ. Therefore, inhibition of angiogenesis induced by tumor and metastasis cells is a promising therapeutic strategy for cancer [32]. Matsubara et al. [33] have studied the effect of vitamin B6 on angiogenesis using an in vitro model, in which rat aortic ring was cultured in collagen gel [34], [35]. This model is used and evaluated as a good model to investigate angiogenesis phenomenon and to find antiangiogenic agents [36], [37]. Microvessels appeared from the edge of aortic ring and elongated in the absence of vitamin B6 (Fig. 3A). The elongation of microvessels was strongly inhibited in the presence of PN and PLP (Fig. 3B–D). PLP showed stronger inhibitory effect than PN. PLP suppressed the elongation of microvessels in a dose-dependent manner. They further studied the effect on the growth of human umbilical vein endothelial cells, being considered to be associated with angiogenesis. The results showed that PLP suppressed the proliferation of endothelial cells, but did not affect the tube formation on reconstituted membrane (Matsubara et al. unpublished results). The antiangiogenic effect appears to be ascribed to antiproliferation activity for endothelium cells. Further in vivo study is necessary to test whether dietary vitamin B6 suppresses colon carcinogenesis by reducing angiogenesis.