Recently, the potential role of vitamins in cancer therapy has attracted considerable research attention. However, the reported findings are inconsistent, with limited information on the biochemical and molecular interactions of different vitamins in various cancer cells. Importantly, the presence of vitamin receptors in tumor cells suggests that vitamins play a significant role in the molecular and biochemical interactions in cancers. Additionally, studies on the efficacy of vitamin supplementation and dosage levels on tumor progression and mortality risk have yielded inconsistent results. Notably, molecular and biochemical investigations have reported the function of vitamins in the proliferation, growth, and invasiveness of tumor cells, as well as in cell cycle arrest and inflammatory signaling. Additionally, different vitamins may regulate the cancer microenvironment by activating various molecular pathways. Vitamins significantly affect immunological function, antioxidant defense, inflammation, and epigenetic control, and can improve treatment outcomes by affecting cell behavior and combating stress and DNA damage. However, further research is necessary to confirm the efficacy of vitamins, establish ideal dosages, and develop effective cancer prevention and treatment plans. Individualized supplementation plans guided by medical knowledge are crucial to achieving optimal results in clinical and preclinical settings. In this review, we critically evaluated the effects of different vitamins on the risk and development of cancer. Additionally, we examined the potential of vitamin supplements to enhance the efficacy of drug therapy and counteract resistance mechanisms that often arise during cancer treatment.

From cell studies, Vitamin K is known to exert anticancer effects on a variety of cancer cell lines, including prostate cancer cells. Recently, we reported an inverse association between dietary intake of menaquinones (vitamin K(2)), but not phylloquinone (vitamin K(1)), and risk of prostate cancer. In this nested case-control study including 250 prostate cancer cases and 494 matched controls, we aimed to confirm this cancer-protective effect using serum undercarboxylated osteocalcin (ucOC), a biomarker of vitamin K status inversely associated with vitamin K intake. In addition, effect modification by a functionally relevant polymorphism in the vitamin K epoxide reductase gene (VKORC1) was assessed. Serum ucOC and intact total osteocalcin (iOC) were analyzed with the use of ELISA tests. Serum ucOC was expressed relative to iOC (i.e., as ucOC/iOC ratio). Conditional logistic regression was used to calculate multivariate adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Serum ucOC/iOC ratio was positively associated with advanced-stage (OR per 0.1 increment, 1.38; 95% CI, 1.03-1.86) and high-grade prostate cancer (OR, 1.21; 95% CI, 1.00-1.46) but not with total prostate cancer. The significant association with advanced-stage prostate cancer was confirmed when serum ucOC/iOC ratio was jointly modeled with menaquinone intake data. There was indication of a lower prostate cancer risk in carriers of the A allele (compared with GG carriers) of the +2255 VKORC1 polymorphism with increasing menaquinone intake (P(interaction) = 0.14) whereas no distinct effect modification was observed for the ucOC/iOC ratio (P(interaction) = 0.37). The increased risks of advanced-stage and high-grade prostate cancer with higher serum ucOC/iOC ratio strengthen the findings for dietary menaquinone intake.

Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2-induced growth inhibition of HCC cells.

HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor kappaB (NF-kappaB) activation was investigated by a NF-kappaB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IkappaB, and an in vitro kinase assay for IkappaB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1.

Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-kappaB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)-, TNF-alpha-, and interleukin (IL)-1-induced activation of NF-kappaB binding and transactivation. Concomitant with the suppression of NF-kappaB activation, vitamin K2 also inhibited the phosphorylation and degradation of IkappaBalpha and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment.

Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IkappaB/NF-kappaB pathway and might therefore be useful for treatment of HCC.