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Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells


Page 687–93

In this study, Watanabe and colleagues correctly hypothesized that the efficacy of 5-fluorouracil (5-FU), a staple drug choice in the treatment of advanced colon cancer, might be enhanced by drugs that, through a different mechanism, reduce the expression of 5-FU's target, thymidilate synthase (TS). This method is of potential clinical utility as it has been shown that cancer cell lines with high levels of TS are not only more resistant to therapy with 5-FU but confer a worse prognosis. Three drugs were evaluated using human colon cancer lines in vitro: fenofibrate, a classic antihyperlipidemia drug; LY294002; and trametinib, a drug currently under review for placement on the market in the USA and EU for treatment of certain types of melanoma. When combined with 5-FU, all three drugs showed marked synergistic effects resulting in increased apoptosis and a decrease in colony formation of cancer cells. doi: 10.1111/cas.12139

FBXO15 regulates P-glycoprotein/ABCB1 expression through the ubiquitin–proteasome pathway in cancer cells


Page 694–702

P-glycoprotein/ABCB1 (P-gp) is a molecule that has been implicated in multidrug-resistant cancer cells. It has been shown to confer resistance to a variety of chemotherapies including vinca alkaloids and anthracyclins by actively transporting these drugs outside the cell, thus reducing their cytotoxic effects. Katayama et al. sought to elucidate the mechanism by which P-gp is regulated. Studying human colon cancer cells in vitro, the researchers found that P-gp was broken down through the ubiquitin–proteosome pathway. It was shown that FBXO15 and Ube2r1 proteins, known for their indirect role in protein degradation, can regulate the amount of P-gp ubiquination, and knockdown of either of these factors results in the upregulation of P-gp. Understanding P-gp and its regulation is important for the development of methods to interfere with the mechanisms of multidrug resistance in cancer cells. doi: 10.1111/cas.12145

Feline sarcoma-related protein expression correlates with malignant aggressiveness and poor prognosis in renal cell carcinoma


Page 681–6

Feline sarcoma-related protein (Fer) is involved in tyrosine kinase signal transduction and plays a role in cell proliferation in certain cancers. Miyata et al. studied the significance of Fer in renal cell carcinoma by combining experiments using in vivo cell culture and human survival data. In cell culture, the authors found that Fer was expressed more prominently in cancer cells than in normal tubules, and that it was positively correlated with cancer proliferation. Furthermore, Fer expression in human specimens correlated with pathological findings, including tumor stage, as well as patient survival. Miyata and colleagues expand on their earlier studies and provide convincing evidence that Fer protein expression plays an important role in tumorigenesis, particularly in renal cell carcinoma. doi: 10.1111/cas.12140