Therefore, hypoxia can lead to a rapid increase in HIF-1α protein levels [163], [166], [167] and [168]. Furthermore, HIF-1α up-regulates a number of important factors for tumor expansion, including VEGF, a key factor in tumor angiogenesis [169], [170] and [171]. In several cancers, overexpression of HIF-1α protein has been found to be associated with tumor aggressiveness and with an unfavorable prognosis [159], [172] and [173]. Hypoxia has also been reported to induce wild-type p53 via a

different pathway than DNA-damaging agents [174]. The hypoxic/anoxic induction of p53 selects Olaparib manufacturer for tumor cells that lack functional p53, and hence evidence diminished apoptotic potential [175]. Elevated levels of HIF-1α are noted in various malignant tumors [159], but it is

unclear whether this is so in oral carcinoma. Therefore, we have examined the implications of HIF-1α expression in HOSCC, in vitro and in vivo. NanoCulture plate system was used to duplicate hypoxic condition within tumor mass of living organisms by the three-dimensional cell culture. As the results, we found that HIF-1α regulates the expression of VEGF, and that HIF-1α may be regulated by p53 in SCC of the oral cavity [176] ( Table 5). Although there are numerous anti-cancer drugs, here, we would daringly like to propose the anti-cancer effect of cimetidine, which is an H2R blocker. Because cimetidine is just a stomach medicine, and it is free of side effects Decitabine such as that the other anti-cancer drugs have. Furthermore, H2R blockers are comprised of cimetidine, famotidine, and ranitidine, however, it is reported that only cimetidine has a precise effect as the anti-cancer drug. In addition, although malignant glandular tumors

are known to be generally resistant to radiation therapy and chemotherapy, the efficacy of cimetidine is observed occasionally in the clinical application Reverse transcriptase for glandular tumor. Therefore, if cimetidine has an effect of anti-cancer drug for oral cancer, it will be ideal drug in this lesion. Cimetidine, the oldest histamine type-2 receptor (H2R) antagonist to be used clinically, is commonly prescribed to treat gastro-esophageal reflux disease as well as gastric and duodenal ulcers [177]. Although it is like a half-remembered drug, it has recently been reported that cimetidine improves the survival of patients with malignant tumors [178] and [179], including gastric [180] and colorectal carcinomas [181]. Cimetidine has been shown to inhibit growth of gastrointestinal cancers via several mechanisms including enhancement of immune activity and inhibition of cancer cell proliferation [179]. Therefore cimetidine may act by enhancing the host immune response against tumor cells [182] and [183] or by blocking the cell growth-promoting activity of histamine [183], [184], [185], [186], [187] and [188]. Kobayashi et al.