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Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) α. We compared the effects of vanadate to PFTα and PFTµ, an inhibitor of transcriptionindependent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcriptionindependent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis. Cancer Res; 70(1); 257-65. ©2010 AACR.

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BACKGROUND Preoperative radiotherapy reduces the rate of local recurrence and improves the chance of survival in patients with resectable, advanced rectal carcinoma. However, because not all tumors respond similarly to radiation, sorting out suitable patients is required to irradiate tumors rationally. The authors examined the possible role of Ku protein in determining tumor radiosensitivity and disease free survival in patients with rectal carcinoma. METHODS The authors studied 96 patients with advanced rectal carcinoma. In preradiation biopsy specimens of tumor samples, the number of cells that were stained positive for Ku protein was evaluated by immunohistochemistry. The expression pattern of Ku protein was examined for an association between tumor radiosensitivity (which was determined according to T classification downstaging, complete pathologic response, or Response Evaluation Criteria in Solid Tumors) and disease free survival. RESULTS There was a high degree of correlation between the percentage of cells that expressed the 70‐kDa Ku protein (Ku70) and the 86‐kDa Ku protein (Ku86) in the tumor sections (correlation coefficient = 0.85; P < 0.001). The expression pattern of Ku protein was correlated not only with tumor radiosensitivity but also with disease free survival. Pathologic TMN classification, histopathologic grade, and Ku70 expression were significant prognostic variables for disease free survival in a multivariate analysis (P = 0.0031, P = 0.030, and P = 0.023, respectively). CONCLUSIONS Ku70 and Ku86 raise the predictive possibility of tumor radiosensitivity. Ku may be a useful parameter for selecting patients with rectal carcinoma for preoperative radiotherapy. Cancer 2002;95:1199–205. © 2002 American Cancer Society. DOI 10.1002/cncr.10807

The DNA double-strand breaks (DSBs) repair pathway has been implicated in maintaining genomic integrity via suppression of chromosomal rearrangements. DNA-dependent protein kinase (DNA-PK) has an important role with DNA DSBs repair. In this study, 93 of untreated cancer patients and 41 of cancer-free healthy volunteers were enrolled. Peripheral blood was collected, separated and centrifuged; DNA-PK activity was measured by DNA-pull-down assay. The expressions of DNA-PKcs, Ku70 and Ku86 were examined by RT-PCR assay and western blotting. Chromosomal aberrations were examined by cytogenetic methods. DNA-PK activities of peripheral blood lymphocytes (PBL) in patients with uterine cervix or breast cancer were significantly lower than those in normal volunteers. Age and smoking had no association with DNA-PK activity, whereas DNA-PK activity and the expression of Ku70, Ku86 and DNA-PKcs in RT-PCR were interrelated. A similar tendency was seen in western blot assay but less clear than in RT-PCR. Therefore, the association between DNA-PK activity and expression of DNA-PK in protein level could not be concluded. The frequency of chromosome aberration, such as dicentric chromosomes and excess fragment increased as the DNA-PK activity decreased. In conclusion, DNA-PK activity is associated with chromosomal instability. DNA-PK activity in PBL is associated with risk of breast and uterine cervix cancer. DNA-PK activity in PBL can be used to select individuals for whom an examination should be performed because of their increased susceptibility to breast and uterine cervix cancer.

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