Modulation of steroid sulfation by celecoxib-like drugs

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DESCRIPTION (provided by applicant): Evidence is mounting that the cyclo-oxygenase (COX) 2 inhibitor, celecoxib, a drug that is widely used to treat osteoarthritis and inflammatory arthritis, has chemo-preventive and chemo-therapeutic effects against breast cancer, colon cancer and lung cancer. As well as inhibiting COX-2, celecoxib interacts with sulfotransferases (SULT). Celecoxib stimulates the 17-sulfation and inhibits the 3-sulfation of estradiol catalyzed by human liver cytosol and by expressed recombinant human sulfotransferase 2A1 (hSULT2A1). Stimulation of 17-sulfation (normally a minor pathway) combined with inhibition of 3-sulfation (normally the major pathway) of estradiol and related estrogens should result in a reduction in the amount of active estrogen available to the breast. Estradiol-3-sulfate, but not 17-sulfate, is a transport form of estradiol that is taken up by the breast where it is hydrolyzed to estradiol. This effect should be beneficial for estrogen- sensitive breast cancers by reducing the uptake of estrogen into the breast. The long-term objective of this research is to ascertain the significance of the effect of celecoxib in modulating sulfation, with respect to its anticarcinogenic activity. This could lead to the development of new therapeutic agents for prevention or treatment of cancer. This small grant application is focused on defining the effect and determining the mechanism. The first specific aim is to examine the structural features of hSULT2A1 substrates, estrogens, androgens and bile acids that make them susceptible to the effect of celecoxib on sulfate conjugation. As well as hSULT2A1, human liver cytosol and expressed recombinant hSULT1A1 and 1E1 will be studied for the effect of celecoxib on their activity. The second specific aim is to study the protein crystallography of hSULT2A1 in the presence and absence of estradiol and celecoxib, so as to ascertain the molecular interaction of the substrate (estradiol) and modulator (celecoxib) with hSULT2A1, with the objective of gaining information on the structural features of celecoxib that induce this change in hSULT2A1 activity. Future research will determine if this in vitro defined effect occurs in human volunteers, and examine molecules related to celecoxib for their interaction with hSULT2A1