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Inhibition of Human Multiple Myeloma Cell Proliferation by
Naltrindole

by
Alexandra Terskiy
M.D./Ph.D. Program

B.A. 2003, Rutgers College

Thesis Advisor: Dr. Richard D. Howells, Ph.D.

Professor

Department: Biochemistry and Molecular Biology

MSB E-609B

Wednesday, May 13, 2009
11:30 a.m.


Abstract

Opioids, such as morphine, are widely used for their analgesic activity; they also modulate the immune system, and display anti-neoplastic effects against a variety of malignancies.
Multiple myeloma is an invasive and incurable plasma cell neoplasm responsible for 10% of all hematological malignancies. Because of its immunologic origin, we hypothesized that human multiple myeloma would be a useful model to study potential antineoplastic properties of opioids. We have screened a variety of opioid compounds for their potential anti-neoplastic activity against multiple myeloma and found that naltrindole, a _-opioid receptor selective antagonist, inhibited the proliferation of several human multiple myeloma cell lines with an EC50 of 16-20 gM, whereas a variety of other cancer cells lines were substantially less sensitive to naltrindole.
[3H]-Naltrindole exhibits saturable, low affinity binding to intact cells and the pharmacological properties of the naltrindole binding site differ significantly from the properties of _-, ۃ{zn or -opioid receptors, leading us to hypothesize that naltrindole inhibits proliferation of multiple myeloma cells through a non-opioid receptor-dependent mechanism.
Regarding naltrindoles mechanism of action, we observed that it inhibits several pathways important for cell survival and proliferation, induces Ca++ influx into the cell, depletes cellular glutathione and induces apoptosis in multiple myeloma cells.
Multiple myeloma cells proliferate in the bone marrow microenvironment, which provides a variety of growth and anti-apoptotic factors, and often affords protection from chemotherapeutic drugs. Importantly for the potential clinical utility of naltrindole, it is able to inhibit multiple myeloma cell proliferation in the presence of bone marrow stromal cells.
Lytic bone lesions associated with multiple myeloma require extensive pain management and opioid analgesics are extensively used. Opioid receptors undergo desensitization and down regulation in response to prolonged agonist exposure, resulting in tolerance to opioids. Analgesic tolerance to morphine is a serious problem in the management of pain. _-Opioid receptor blockade through either genetic or pharmacological means attenuates morphine tolerance without interfering with its analgesic efficacy. We propose that naltrindole will be a useful antineoplastic agent, as well as attenuate tolerance to morphine, thereby improving the quality of life for patients with multiple myeloma.


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