The emergence of anticancer drug resistance constitutes a major problem in the successful treatment of disseminated cancer. Frequently, in both clinical and experimental systems of anticancer drug treatment, exposure to one anticancer drug results in the development of cancer cells that are resistant to multiple drugs in addition to the selecting drug used in treatment. This phenomenon is termed multidrug resistance (MDR) and is associated with the increased expression of a number of genes believed to contribute to the MDR phenotype.

A major focus of our research concerns the roles in the emergence of cancer drug resistance of certain drug metabolizing enzymes and the membrane-associated transporters that remove drugs and their metabolites from cells. In particular, we are interested in how the combined expression of glutathione transferases (GST)–drug conjugating enzymes–and the multidrug resistance proteins (MRP)–a family of drug and drug-conjugate efflux transporters–influence drug resistance in cancer cells. Additionally, as the chemical properties and toxicities of many cancer drugs and carcinogens overlap, we are also investigating how the interplay between GST and MRP effects the sensitivity of cells to carcinogen exposure. Using a variety of model cell lines developed in our laboratory, we are exploring the hypothesis that MRP and GST act synergistically to confer both drug resistance in cancer cells and carcinogen resistance in normal cells.

More recently, we have begun investigating the role of glutathione conjugation and conjugate removal in the modulation of the biological, including anti-tumor, activities of potent cellular eicosinoids–signaling molecules derived from arachidonic acid.

Recent publications:

Charles S. Morrow, Christina Peklak-Scott, Bimjhana Bishwokarma, Pamela K. Smitherman, and Alan J. Townsend. Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol. Pharm. 69: 1499-1505, 2006.

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. 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.

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.

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.

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.

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 PPARγ activation. Biochemistry 48:492-498, 2009.