Future investigations of vorinostat as possible radiosensitizing agent might be within a long-term curative radiotherapy protocol, for example as an additional component of neoadjuvant chemoradiotherapy for LARC. The confirmed presence of MYC expression in the intended radiotherapy target tissue in LARC patients encourages future exploration of this proto-oncogene as a novel biomarker endpoint. The myc protein acts both as DG-172 dihydrochloride supplier transcriptional activator and repressor, regulating a myriad of genes that collectively conduct cell cycle progression, apoptosis, angiogenesis, and genetic instability. Specifically, it has been suggested that myc activates DNA damage repair genes, and interestingly, that myc in hypoxic tumors acts synergistically with the transcription factor hypoxia-inducible factor type 1a, HIF-1a. Recent evidence indicates that HDAC inhibition suppresses HIF-1a activity. Consequently, mitigation of DNA damage repair capacity through suppression of myc/HIF-1a synergy in hypoxic tumors, typically being resistant to radiation, provides an appealing explanation for the radiosensitizing effect of HDAC inhibitors. However, conflicting data have been presented as to how HDAC inhibition may influence the myc protein itself. Whereas inhibition of various HDAC 883065-90-5 enzymes has been shown to cause myc repression in a range of human cancer cell lines, which corresponds well with the data in the present study, specific nuclear induction of myc to mediate HDAC inhibitor-induced apoptosis in glioblastoma cell lines has also been demonstrated. Interestingly, in nasopharyngeal carcinoma cells that were resistant to radiation, myc was found to be essential through the transcriptional activation of cell cycle checkpoint kinases, which are signaling factors implicated in DNA damage repair, thereby facilitating tumor cell survival following radiation exposure. On the contrary, although radiosensitization was conferred by HDAC inhibition both in hypoxic and normoxic hepatocellular carcinoma cells, a lower level of myc expression was associated with the hypoxic and more radioresistant condition. Of particular note, in the present study, the vorinostat-induced repression of MYC was found both in study patients�� PBMC, clearly representing normoxic tissue
