Cass, Carol - University of Alberta - Department of Biochemistry

研究领域

Nucleoside Transporter Proteins and their Roles in Nucleoside Biology and Therapeutics I study nucleoside transporter proteins and their roles in nucleotide metabolism, with a focus on nucleoside drugs used in cancer chemotherapy. Examples of clinically important anticancer nucleoside drugs are capecitabine, cladribine, clofarabine, cytarabine, fludarabine, and gemcitabine. I am also interested in the role of nucleoside transporters in cell signaling by adenosine. I have worked on nucleoside transport processes since 1970, beginning shortly after the discovery of mediated transport of nucleosides by my postdoctoral mentor, Dr. A.R.P. Paterson, at the University of Alberta. In a long-term discovery research collaboration with Drs. J.D. Young (University of Alberta) and S.A. Baldwin (University of Leeds, UK), we were among the first to describe and characterize nucleoside transporter proteins. We are now applying molecular knowledge of the transporter proteins to studies of the pharmacology of nucleoside drugs in collaboration with clinical colleagues at the Cross Cancer Institute and elsewhere. Our fundamental discovery research has been directed towards understanding the mechanisms of transport of nucleosides across biological membranes, and the role of nucleoside transporter proteins in the biology of nucleosides. Our translational applied research has been directed towards understanding the role of nucleoside transporters in the pharmacology of nucleoside drugs, with a focus on relationships between the abundance of nucleoside transporter proteins and resistance to nucleoside drugs. Our goal is to develop strategies to guide clinicians in the use of nucleoside drugs in treatment of cancer. Although I no longer maintain an independent research laboratory, I continue to have active collaborations in nucleoside therapeutics with colleagues in the Department of Oncology (Drs. Michael B. Sawyer, John R. Mackey) and the Department of Physiology (Dr. J.D. Young) at the University of Alberta.

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Zhang, J., Visser, F.,King, K.M., Baldwin, S.A., Young, J.D. and Cass, C.E. The role of nucleoside transporters in cancer chemotherapy with nucleoside drugs. Cancer and Metastasis Reviews. Cancer Metastasis Rev. 26: 85-110 (2007). Baldwin, S.A., McConkey, G.A., Cass, C.E. and Young, J.D. Nucleoside transport as a potential target for chemotherapy in malaria. Curr Pharm Des. 13: 569-580 (2007). Young, J.D., Yao, S.Y.M., Sun, L., Cass, C.E. and Baldwin, S. ENT family of nucleoside and nucleobase transporter proteins. Xenobiotica Special Edition entitled “Structure, Function and Regulation of Transporters.” 38:995-1021 (2008). Damaraju, V.L., Sawyer, M.B., Mackey, J.R., Young, J.D. and Cass, C.E. Human nucleoside transporters: biomarkers for response to nucleoside drugs. Invited article for special Issue commemorating the 70th birthday of Dr. M.J. Robins. Nucleosides, Nucleotides and Nucleic Acids. 28:450-463 (2009). Parkinson, F.E., Damaraju, V.L., Graham, K., Yao, S.Y.M., Baldwin, S.A., Cass, C.E. and Young, J.D. Molecular biology of nucleoside transporters and their distributions and functions in the brain. Current Topics in Medicinal Chemistry. 11(8):948-972 (2011). Young, J.D., Yao, S.Y.M., Baldwin, J., Cass, C.E. and Baldwin, S.A. The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Molecular Aspects of Medicine, Special Edition on Transporters and Channels and Related Pathologies. In press (April 11, 2012). Visser, F., Sun, L., Damaraju, V., Tackaberry, T., Peng, Y., Robins, M.J., Baldwin, S.A., Young, J.D. and Cass, C.E. Residues 334 and 338 in transmembrane segment 8 of human equilibrative nucleoside transporter 1 are important determinants of inhibitor sensitivity, protein folding and catalytic turnover. J. Biol. Chem. 282:14148-14157 (2007). Damaraju, V.L., Elwi, A.N., Hunter, C., Carpenter, P., Santos, C., Barron, G.M., Sun, X.J., Young, J.D., Mackey, J.R., Sawyer, M.B. and Cass, C.E. Localization of broadly selective equilibrative and concentrative nucleoside transporters, hENT1 and hCNT3, in human kidney. Amer. J. Physiol.- Renal Physiol. 293:F200-F211 (2007). Damaraju, V.L., Bouffard, D.Y., Wong, C.K.W., Clarke, M.L., Mackey, J.R., Leblond, L., Cass, C.E. and Gourdeau, H. Synergistic Activity of Troxacitabine (Trosatyl™) and Gemcitabine in Pancreatic Cancer. BMC Cancer. 7:121 (2007). Smith, K.M., Slugoski, M.D., Cass, C.E., Baldwin, S.A., Karpinski, E. and Young, J.D. Cation coupling properties of human concentrative nucleoside transporters hCNT1, hCNT2 and hCNT3. Mol. Membrane Biol. 24:53-64 (2007). Slugoski, M.D., Loewen, S.K., Ng, A.M., Smith, K.M., Yao, S.Y., Karpinski, E., Cass, C.E., Baldwin, S.A. and Young, J.D. Specific mutations in transmembrane helix 8 of human concentrative Na+/nucleoside cotransporter hCNT1 affect permeant selectivity and cation coupling. Biochem. 46: 1684-1693 (2007). Yao, S.Y.M., Ng, A.M.L., Slugoski, M.D., Smith, K.M., Mulinta, R., Karpinski, E., Cass, C.E., Baldwin, S.A. and Young, J.D. Conserved glutamate residues are critically involved in Na+/nucleoside cotransport by human concentrative nucleoside transporter 1 (hCNT1). J. Biol. Chem. 282:30607-30617 (2007). Paproski, R.J., Visser, F., Zhang, J., Tackaberry, T., Damaraju, V., Baldwin, S.A., Young, J.D. and Cass, C.E. Mutation of Trp 29 of human equilibrative nucleoside transporter 1 alters affinity for coronary vasodilator drugs and nucleoside selectivity. Biochem J., 414:291-300 (2008). Cai, J., Damaraju, V.L., Groulx, N., Mowles, D., Peng, Y., Robins, M.J., Cass, C.E. and Gros, P. Two distinct molecular mechanisms underlying cytarabine resistance in human leukemic cells. Cancer Res. 68:2349-2357 (2008). Damaraju, D., Damaraju, V.L., Brun, M., Mowles, D., Kuzman, M., Berendt, R.C., Sawyer, M.B. and Cass, C.E. Cytotoxic activities of nucleoside and nucleobase analog drugs in malignant mesothelioma: characterization of a novel nucleobase transport activity. Biochem. Pharmacol. 75(10):1901-1911 (2008). Paproski, R.J., Ng., A.M.L., Yao, S.Y.M., Graham, K., Peng, Y., Robins, M.J., Young, J.D. and Cass, C.E. The role of human nucleoside transporters in uptake of 3'-deoxy-3'-fluorothymidine. Mol. Pharmacol. 74:1372-1380 (2008). Slugoski, M.D., Ng, A.M.L., Yao, S.Y.M., Smith, K.M., Lin, C.C., Zhang, J., Karpinski, E., Cass, C.E., Baldwin, S.A. and Young, J.D. A proton-mediated conformational shift identifies a mobile pore-lining cysteine residue (C561) in human concentrative nucleoside transporter 3 (hCNT3). J. Biol. Chem. 283(13):8496-8507 (2008). Slugoski, M.D., Smith, K.M., Mulinta, R., Ng, A.M.L., Yao, S.Y.M., Morrison, E.L., Lee, Q.O.T., Zhang, J., Karpinski, E., Cass, C.E., Baldwin, S.A. and Young, J.D. A conformationally mobile cysteine residue (C561) modulates Na+- and H+-activation of human concentrative nucleoside transporter 3 (hCNT3). J. Biol. Chem. 283:24922-24934 (2008). Elwi, A.N., Damaraju, V.L., Kuzma, M.L., Baldwin, S.A., Young, J.D., Sawyer, M.B. and Cass, C.E. Human concentrative nucleoside transporter 3 is a determinant of fludarabine transportability and cytotoxicity in primary cultures of human kidney proximal tubule cells. Cancer Chemother. Pharmacol. 63(2):289-301 (2009). Elwi, A.N., Damaraju, V.J., Kuzma, M.L., Mowles, D.A., Baldwin, S.A., Young, J.D., Sawyer, M.B. and Cass, C.E. Transepithelial fluxes of adenosine and 2’-deoxyadenosine across human renal proximal tubule cells: roles of nucleoside transporters hENT1, hENT2, and hCNT3. Am. J. Physiol.- Renal Physiol. Slugoski, M.D., Smith, K.M., Ng, A.M.L., Yao, S.Y.M., Karpinski, E., Cass, C.E., Baldwin, S.A. and Young, J.D. Conserved glutamate residues E343 and E519 provide mechanistic insights into cation/nucleoside cotransport by human concentrative nucleoside transporter 3 (hCNT3). J. Biol. Chem. 284:17266-17280 (2009). Slugoski, M.D., Ng, A.M.L., Yao, S.Y.M., Mulinta, R., Cass, C.E., Baldwin, S.A. and Young, J. D. Substituted cysteine accessibility method (SCAM) analysis of human concentrative nucleoside transporter hCNT3 reveals a novel discontinuous region of functional importance within the CNT family motif (G/A)XKX₃NEFVA(Y/M/F). J. Biol. Chem. 284:17281-17292 (2009). Damaraju, S., Damaraju, V.L., Mowles, D., Sawyer, M.B., Damaraju, S. and Cass, C.E. Cytotoxic activity of gemcitabine in cultured cell lines derived from histologically different types of bladder cancer: role of thymidine kinase 2. Biochem. Pharmacol. 79(1):21-29 (2010).