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In inflammatory bowel disease, chronic inflammation results in the development of colon cancer known as colitis-associated cancer. This disease is associated with tumor necrosis factor-α (TNF-α) signaling. In addition, intestinal fibrosis is a common clinical complication that is promoted by transforming growth factor β1 (TGF-β 1 ). In our previous study, MA-35 attenuated renal fibrosis by inhibiting both TNF-α and TGF-β 1 signaling. This study aimed to identify the possible antitumor effects and antifibrotic effects of MA-35 using an AOM/DSS mouse model. MA-35 was orally administered every day for 70 days in the AOM/DSS mouse model. There was no difference in weight loss between the AOM/DSS group and the AOMDSS + MA-35 group, but the disease activity index score and the survival rate were improved by MA-35. MA-35 blocked the anemia and shortening of the colon induced by AOM/DSS. MA-35 reduced the macroscopic formation of tumors in the colon. In the microscopic evaluation, MA-35 reduced inflammation and fibrosis in areas with dysplasia. Furthermore, the TNF-α mRNA level in the colon tended to be reduced, and the interleukin 6, TGF-β 1 and fibronectin 1 mRNA levels in the colon were significantly reduced by MA-35. These results suggested that MA-35 inhibited AOM/DSS-induced carcinogenesis by reducing inflammation and fibrosis.

Case 1: A female patient in her 60s underwent laparoscopic intersphincteric resection for rectal cancer. After 42 months, the serum level of carcinoembryonic antigen(CEA)was elevated, and PET-CT showed a locally recurrent rectal cancer that increased FDG-uptake. Carbon ion radiotherapy(CIRT)(73.6 GyE/16 Fr)was performed. Serum CEA level and FDG-uptake were normalized. No regrowth of tumor has been found for 12 months. Case 2: A female patient in her 60s underwent abdominoperineal resection for rectal cancer. After 42 months, the serum level of CEA was elevated, and CT revealed a local recurrence of rectal cancer. Subsequently, the tumor was resected; however, resection margin was microscopically positive. Therefore, chemoradiotherapy(S-1, 60 Gy)was performed. At 31 months after local resection, a re-recurrent tumor was noted in her left ischium. Therefore, CIRT(70.4 GyE/16 Fr)was performed. Serum CEA level and FDG-uptake were normalized. No regrowth of tumor has been found for 24 months. CIRT is an effective therapy for locally recurrent rectal cancer.

Background: BRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done., Methods: GBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection., Results: BAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8%) and showed a strong trend toward a worse median survival time of 13.3 months (95% CI, 17.6-62.6) (p = 0.0034). Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis., Conclusion: Our findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC., Competing Interests: The authors have declared that no competing interests exist.

Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of 24 synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2. The screening of the 24 synthetic analogs by means of flow cytometry revealed that four of the curcumin analogs (GO-Y030, GO-Y078, GO-Y168, and GO-Y172) significantly inhibited the efflux of the ABCG2 substrates, mitoxantrone and pheophorbide A, from ABCG2-overexpressing K562/breast cancer resistance protein (BCRP) cells. Biochemical analyses showed that GO-Y030, GO-Y078, and GO-Y172 stimulated the ATPase activity of ABCG2 at nanomolar concentrations and inhibited the photolabeling of ABCG2 with iodoarylazidoprazosin, suggesting that these analogs interact with the substrate-binding sites of ABCG2. In addition, when used in cytotoxicity assays, GO-Y030 and GO-Y078 were found to improve the sensitivity of the anticancer drug, SN-38, in K562/BCRP cells. Taken together, these results suggest that nontoxic synthetic curcumin analogs with increased bioavailability, especially GO-Y030 and GO-Y078, inhibit the function of ABCG2 by directly interacting at the substrate-binding site. These synthetic curcumin analogs could therefore be developed as potent modulators to overcome ABCG2-mediated MDR in cancer cells., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)