Cellular thymidine metabolism involves two pathways: the catabolic and salvage pathways. The catabolic pathway breaks down thymidine to carbon dioxide for energy while the salvage pathway converts thymidine to its 5′-triphosphate as one of building blocks for DNA synthesis. Cytosolic level of thymidine is regulated by both thymidine phosphorylase (TYMP) of the catabolic pathway and thymidine kinase (TK) of the salvage pathway. In tumor tissues and cancer cells, abnormally high levels of these two proteins have been consistently reported. Therefore, thymidine metabolic pathways in cancer cells are a potential therapeutic target for novel drug design and development. We recently developed a novel thymidine analog, 3′-deoxythymidine phenylquinoxaline conjugate (dT-QX) that selectively killed a series of cancer cell lines including human liver carcinoma HepG2 and Hep3B, breast adenocarcinoma MCF-7, rat brain glioma C6 and mouse liver cancer H22 cells and showed low cytotoxicity on the normal liver hepatocyte HL-7702 cells. dT-QX is a conjugate of 3′-deoxythymidine and a DNA intercalating moiety with a triazole linkage achieved by click chemistry. The selective killing of cancer cells was attributed to the selective inhibition of DNA synthesis in the cancer cells but not in normal liver HL-7702 cells, resulting in extensive production of mitochondrial superoxide stress. The conjugation of 3′-deoxythymidine was found to be critical for dT-QX to achieve the selective killing of cancer cells. The killing by dT-QX was revealed to be directly due to the expression levels of TYMP and TKs in cancer cells, confirming that dT-QX successfully targeted the thymidine metabolic pathways as designed. Finally, a preliminary mouse study with subcutaneous liver tumors confirmed that dT-QX effectively inhibited the growth of tumors in vivo.
Citation Format: Qibing Zhou, Qiong Wei, Dejun Zhang. Targeting thymidine metabolic pathways in cancer cells with a novel thymidine conjugate. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5503. doi:10.1158/1538-7445.AM2013-5503