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"Exploration of the Mechanisms Involved in the Antiproliferative Activity of Naltrindole"

by
Jyoti Joshi Mundra
Biochemistry and Molecular Biology Program
B.S. 2003, University of Delhi, India
M.S. 2005, University of Delhi, India
M.S. 2008, State University of New York at Buffalo



Thesis Advisor: Richard D. Howells, Ph.D.
Professor
Department of Biochemistry and Molecular Biology

Monday, June 11, 2012
12:00 P.M., , MSB E-609b


Abstract

It has previously been demonstrated that immune cell activation and proliferation was sensitive to the effects of naltrindole, a non-peptidic -opioid receptor selective antagonist, therefore, we hypothesized that human multiple myeloma (MM) would be a valuable model to study potential antineoplastic properties of naltrindole. [3H]- Naltrindole exhibited saturable, low affinity binding to intact human MM cells, however, the pharmacological profile of the binding site differed considerably from the properties of , and opioid receptors, and opioid receptor mRNA was not detected in MM cells by reverse transcriptase polymerase chain reaction. Naltrindole inhibited the proliferation of human U266 MM cells in a time- and dose-dependent manner with an EC50 of 10-20 M. Additive inhibition of MM cell proliferation was observed using a combination of naltrindole with the histone deacetylase inhibitor, sodium valproate, the proteasome inhibitor, bortezomib, the glucocorticoid receptor agonist, dexamethasone, and 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, simvastatin. Treatment of U266 cells with naltrindole significantly decreased the level of the active, phosphorylated form of the kinases, ERK and Akt, which may be related to its antiproliferative activity. The antiproliferative activity of naltrindole toward MM cells was maintained in co-cultures of MM and bone marrow-derived stromal cells, mimicking the bone marrow microenvironment. In vivo, daily intraperitoneal injection of naltrindole significantly decreased the growth of tumors using human MM cell xenografts in SCID mice.
While investigating the mechanism of action of naltrindole, we have observed that it rapidly increases intracellular calcium levels in MM cells at doses which are similar to its EC50 for inhibition of cell proliferation, and the calcium appears to be released from the endoplasmic reticulum. In addition, naltrindole inhibits capacitative Ca2+ influx induced by a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, thapsigargin, which could also be the potential mechanism for its inhibition of proliferation of MM cells. We have also shown that naltrindole decreases proliferation and inhibits voltage-gated sodium and potassium channels in AtT-20 cells, a murine neuroendocrine pituitary tumor cell line.
Naltrindole, therefore, has the potential to be an important addition to current MM therapies.


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