Targeting thymidine phosphorylase inhibition in human colorectal cancer xenografts.

Human thymidine phosphorylase (hTP) is overexpressed in several solid tumors and is commonly associated with aggressiveness and unfavorable prognosis. 6-(((1,3-Dihydroxypropan-2-yl)amino)methyl)-5-iodopyrimidine-2,4(1H,3H)-dione (CPBMF-223) is a noncompetitive hTP inhibitor, which has been described as a tumor angiogenesis inhibitor. The present study investigated the effects of CPBMF-223 in a xenograft tumor induced by human colorectal carcinoma cells (HCT-116). Additionally, CPBMF-223 capacity to reduce cell migration, its toxicological profile, and pharmacokinetic characteristics, were also evaluated. The intraperitoneal treatment with CPBMF-223 markedly prevented the relative tumor growth with an efficacy similar to that observed for 5-fluorouracil. Interestingly, number of vessels were significantly decreased in the treated groups. Moreover, CPBMF-223 significantly reduced the migration of cell line HCT-116. In the Ames assay and in an acute oral toxicity test, the molecule did not alter any evaluated parameter. Using the zebrafish toxicity model, cardiac and locomotor parameters were slightly changed. Regarding the pharmacokinetics profile, CPBMF-223 showed clearance of 9.42 L/h/kg after intravenous administration, oral bioavailability of 13.5%, and a half-life of 0.75 h. Our findings shed new light on the role of hTP in colorectal cancer induced by HCT-116 cell in mice, pointing out CPBMF-223 as, hopefully, a promising drug candidate.

Cytotoxic Effects of Diclofenac and Ibuprofen Zinc (II)-Nicotinamide Ternary Complexes in Breast Cancer Cell Lines

Abstract Breast cancer is one of the leading types of cancer worldwide, and the search for new treatment options are crucial. Nonsteroidal anti-inflammatory drugs (NSAIDs) -specially ibuprofen and diclofenac-, have shown antitumoral effect against several types of cancer. The synthesis of organometallic compounds has shown significant improvements in pharmacological properties and efficacy of organic molecules. Two zinc II ternary complexes containing the NSAIDs diclofenac and ibuprofen and nicotinamide neutral linker (Nic) were obtained by the two-step solvent metalligand complexation method. The compounds Zn2(Diclof)4(Nic)2 (complex 1) and Zn2(Ibup)4(Nic)2 (complex 2) were tested in breast cancer cell lines (4T1, MCF-7 and MDA-MB-231) to evaluate their cytotoxicity, comparing to ibuprofen and diclofenac as controls. We found that both complex 1 and 2 exerted more than 60% reduction in 4T1 viability at 250µM, and complex 2 decreased cell viability at 250 µM and 137.5 µM in MCF-7 (34.35% and 26.42% reduction, respectively) and in MDA-MB-231 (57.2% and 22.88% reduction, respectively), all compared to controls. Complex 1 was selective only in MCF-7, and complex 2 was selective in both MCF-7 and MDA-MB-231. In summary, our data showed that the cytotoxic effect of complex 1 and 2 is increased comparing to their original NSAID in different breast cancer cell lines, highlighting their potential anti-tumoral activity.