The emergence of anticancer drug resistance constitutes a major problem in the successful treatment of advanced or disseminated cancers with conventional cancer drugs. Hence, a major focus of our research has been to understand the roles in the emergence of cancer drug resistance of the drug metabolizing enzymes and the membrane-associated transporters that remove drugs and their metabolites from cells. In particular, we have been interested in how combined expression of glutathione transferases (GST)––drug conjugating enzymes––and multidrug resistance proteins (MRP)––a family of drug and drug conjugate efflux transporters––influence drug resistance in cancer cells. Additionally, as the chemical properties of cancer drugs, carcinogens, and other cellular toxins frequently overlap, we have also investigated how the interplay between GST and MRP affects the sensitivity of cells to carcinogen exposure. Indeed our laboratory has shown that, for many cancer drugs, carcinogens, and other toxins, GST and MRP can act cooperatively, and often in synergy, to confer drug resistance in cancer cells and carcinogen resistance in normal cells.

More recently, we have shown that MRP and GST can modulate the activities of some potent and chemically reactive lipid signaling molecules including the oxo- and nitro-derivatives of endogenous unsaturated fatty acids.

Inspired by these and other studies, additional areas of ongoing research include a clinical study to determine the prognostic significance of MRP and GST expression in chronic leukemia and a preclinical study to evaluate novel approaches to the treatment of breast cancer using conventional chemotherapeutic drugs in combination with lipid and pharmaceutical signaling molecules.

Recent publications:

M. J. Gorczynski, P. K. Smitherman, T. E. Akiyama, H. B. Wood, J. P.  Berger, S. B. King, C. S. Morrow. Activation of peroxisome proliferator-activated receptor ? (PPAR?) by nitroalkene fatty acids:  Importance of nitration position and degree of unsaturation. J. Med.  Chem. 52: 4631-4639, 2009.

D. J. P. Bates, M. O. Lively, M. J. Gorczynski, S. B. King, A. J. Townsend, and C. S. Morrow. Non-catalytic interactions between glutathione S-transferases and nitroalkene fatty acids modulate nitroalkene-mediated activation of PPARg. Biochemistry 48: 4159-4169, 2009.

Richard L. Alexander, Marcus W. Wright, Michael J. Gorczynski, Pamela K. Smitherman, Taro E. Akiyama, Harold B. Wood, Joel P. Berger, S. Bruce King, and Charles S. Morrow Differential potencies of naturally occurring regioisomers of nitrolinoleic acid in PPAR? activation. Biochemistry 48: 492-498, 2009.

C. Peklak-Scott, P. K. Smitherman, A. J. Townsend, and C. S. Morrow. The role of glutathione S-transferase P1-1 (GSTP1-1) in the cellular detoxification of cisplatin. Molecular Cancer Therapeutics 7:3247-3255, 2008.

M. B. Sibhatu, P. K. Smitherman, A. J. Townsend, and C. S. Morrow. Expression of MRP1 and GSTP1-1 modulate the acute cellular response to treatment with the chemopreventive isothiocyanate, sulforaphane. Carcinogenesis 29: 807-815, 2008.

R. L. Alexander_, D. J. P. Bates, M. Wright, S. B. King, and C. S. Morrow. Modulation of nitrated lipid signaling by multidrug resistance protein 1 (MRP1): Glutathione conjugation and MRP1-mediated efflux inhibit nitrolinoleic acid-induced, PPARg-dependent transcription activation. Biochemistry 45: 7889-7896, 2006.

C. S. Morrow, C. Peklak-Scott, B. Bishwokarma, P. K. Smitherman, and A. J. Townsend. Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Molecular Pharmacology 69: 1499-1505, 2006.

C. Peklak-Scott, A. J. Townsend, and C. S. Morrow. Dynamics of glutathione conjugation and conjugate efflux in detoxification of the carcinogen, 4-nitroquinoline 1-oxide: Contributions of glutathione, glutathione S-transferase, and MRP1. Biochemistry 44: 4426-4433, 2005.

P. K. Smitherman,  A. J. Townsend, T. E. Kute, and C. S. Morrow,  Role of multidrug resistance protein 2 (MRP2, ABCC2) in alkylating agent detoxification: MRP2 potentiates glutathione S-transferase A1-1 resistance to chlorambucil cytotoxicity. Journal of Pharmacology and Experimental Therapeutics, 308: 260-267, 2004.

C.M. Paumi, P.K. Smitherman, A.J. Townsend, and C.S. Morrow. Glutathione S-transferases (GST) inhibit transcriptional activation by the peroxisomal proliferator-activated receptor (PPAR) ligand, 15-deoxy-^12,14prostaglandin J₂ (15-d-PGJ₂). Biochemistry 43: 2345-2352, 2004.

C.M. Paumi, M. Wright, A.J. Townsend, C.S. Morrow. Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-^12,14prostaglandin J₂ in MCF7 breast cancer cells. Biochemistry 42: 5429-5437, 2003.

Paumi, C.M., B.G. Ledford, P.K. Smitherman, A.J. Townsend, C.S. Morrow. Role of multidrug resistance protein 1 (MRP1) and glutathione S-transferase A1-1 in alkylating agent resistance: Kinetics of glutathione conjugate formation and efflux govern differential cellular sensitivity to chlorambucil versus melphalan toxicity. J. Biol. Chem. 276: 7952-7956, 2001.