Rita Mukhopadhyay, Ph.D.

Leishmaniasis:

Leishmaniasis is a protozoan parasitic infection affecting almost 12 million people world-wide. The arsenic related metal antimony containing compounds like Pentostam and Glucantime are the first line of treatment against this disease. Drug resistance has frequently been reported in field isolates and clinical resistance is a major impediment to the treatment of this disease. Our previous studies in this parasite have shown that drug resistance is an interplay between overexpression of thiols, efflux and intracellular sequestration. One way in which drug resistance can arise is through mutation or downregulation of the drug uptake system(s). To date no uptake systems for either arsenic or antimony drugs have been identified in Leishmania. In bacteria, yeast and mammals arsenite and antimonite uptake systems are aquaglyceroporins. We have recently identified the genes for an aquaglyceroporin homologue, LTAQP1 and LMAQP1, in Leishmania tarentolae and Leishmania major respectively. The gene products have all the signature motifs of aquaglyceroporins and are candidates for arsenite/antimonite uptake systems of Leishmania.

Leukemia:

Leukemia is the most common childhood cancer. Each year in the United States more than 200,000 children and adults are diagnosed with leukemia or lymphoma, and half die of their disease. In early 1990s, with the advent of all-trans-retinoic-acid (ATRA) therapy, the survival of the patients with acute promyelocytic leukemia (APL) greatly increased. However, 20-30% of patients treated with ATRA relapsed. Arsenic trioxide is now being used to treat APL and other types like CML and ALL. In spite of the advancement of treatment 20-25% children die. Drug resistance is the major impediment to the treatment of cancer including leukemia. Arsenic trioxide is widely used against hematological malignancies as well as solid tumors and resistance to this drug has been reported. In collaboration with Children’s Hospital of Michigan and Karmanos cancer center, we are looking at the mechanisms of arsenic resistance in leukemia cells in vitro and in vivo. In vitro we are selecting arsenite resistant leukemia cell lines and in vivo we will characterize patient cells that are sensitive and refractory to arsenite treatment.

Mukhopadhyay, R., Shi, J., and Rosen, B. P. Purification and characterization of Acr2p, the Saccharomyces cerevisiae arsenate reductase. J. Biol. Chem. 275, 21149-21157 (2000).

L gar , D., Richard, D., Mukhopadhyay, R., Stierhof, Y., Rosen, B. P., Haimeur, A., Papadopoulou, B and Ouellette, M. The Leishmania ATP-binding cassette protein PGPA is an intracellular metal-thiol transporter ATPase. J. Biol. Chem. 276, 26301-26307 (2001).

Mukhopadhyay, R and Rosen, B. P. The phosphatase C(X)5 R motif is required for the catalytic activity of the Saccharomyces cerevisiae Acr2p arsenate reductase. J. Biol. Chem. 276, 34738-34742 (2001).

Liu Z., Shen J., Carbrey J. M., Mukhopadhyay R., Agre P. and Rosen B. P. Arsenite transport by mammalian aquaglyceroporins AQP7 and AQP9. Proceedings of National Academy of Sciences, 99, 6053-6058 (2002).

Rosen B. P., Zhou Y. and Mukhopadhyay R. Directed evolution of a yeast arsenate reductase into a protein tyrosine phosphatase. J. Biol. Chem. (2003) (In press).