(I) Interplay between N-ethylmaleimide and arsenic on poly(ADP-ribosyl)ation (II) Association of change in plasma TGF-β1 levels with the oncological outcome of patients with localized prostate cancer treated with prostate cryoablation

• Main Authors: Wang, Alexander Sheng-Shin, 王聖鑫
• Other Authors: Pu, Yeong-Shiau
• Format: Others
• Language: zh-TW
• Published: 2016
• Online Access: http://ndltd.ncl.edu.tw/handle/17361013644753457136

博士 === 國立清華大學 === 生物科技研究所 === 105 === (I) Long term exposure to arsenic has been known to induce neoplastic initiation and progression in several organs; however, the role of arsenic in oxidative stress-mediated DNA damage remains elusive. One of the immediate cellular responses to DNA damage is poly(ADP-ribosyl)ation (PARylation), which mediates DNA repair and enhances cell survival. In this study, we found that oxidative stress (H2O2)-induced PARylation was suppressed by arsenic (As2O3) exposure in different human cancer cells. Moreover, As2O3 treatment promoted H2O2-induced DNA damage and apoptosis, leading to increased cell death. We found that N-ethylmaleimide (NEM), an organic compound derived from maleic acid, can reverse As2O3-mediated effects, thus enhancing PARylation with attenuated cell death and increased cell survival. Pharmacologic inhibition of glutathione (GSH) with L-buthionine-sulfoximine blocked the antagonistic effect of NEM on As2O3, thereby continuing As2O3-mediated suppression of PARylation and causing DNA damage. Our findings identify NEM as a potential antidote against arsenic-mediated DNA damage in a GSH dependent manner. (II) Purpose: To evaluate the cytokine transforming growth factor beta 1 (TGF-β1) as a predictor of oncological outcomes in patients after cryoablation. Materials and Methods: Perioperative blood samples from prostate cancer (PC) patients who underwent total gland cryoablation between October 2011 and March 2013 were collected prospectively. Plasma TGF-β1 levels were quantified using magnetic bead immunoassay. The perioperative change in TGF-β1 was defined as the change in TGF-β1 from before surgery to 1–2 months after surgery. Biochemical recurrence (BCR) was defined according to the Phoenix criteria. The Mann–Whitney U, Kruskal–Wallis rank sum, and Chi-square test were used to compare the clinical characteristics of the subsets. The Cox proportional hazard model was applied for the comparison of recurrence risk among the groups. Results: A total of 75 PC patients were included. During a median follow-up period of 12 months (range: 2.5–47 months), 11 patients had BCR, and 64 patients did not. Significantly greater changes in the perioperative TGF-β1 levels (median: 470.3 vs. 78.9 pg/ml) were observed in patients with than without BCR (p < 0.05). According to the changes in TGF-β1 levels, the patients were further divided into 4 groups, which were determined in the quartile categories of perioperative TGF-β1 levels. Group 4 (≥430) predicted the worst BCR outcome. Conclusions: Perioperative plasma TGF-β1 levels were associated with BCR after prostate cryoablation for localized PC. Increase in postoperative plasma TGF-β1 may be a novel predictor for poor oncological outcomes and prompt a more aggressive follow-up or earlier salvage treatment.