Abstract
It has previously been demonstrated that immune cell activation and proliferation was sensitive to the effects of naltrindole, a non-peptidic δ-opioid receptor selective antagonist, therefore, we hypothesized that human 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 δ, κ and μ opioid receptors, and opioid receptor mRNA was not detected in MM cells by RT-PCR. Naltrindole inhibited the proliferation of cultured human U266 MM cells in a time- and dose-dependent manner with an EC50 of 16 μM. The naltrindole induced inhibition of U266 cell proliferation was not blocked by a 10-fold molar excess of naltrexone, a non-selective opioid antagonist. Additive inhibition of MM cell proliferation was observed using a combination of naltrindole with the HDAC inhibitor, sodium valproate, the proteasome inhibitor, bortezomib, the glucocorticoid receptor agonist, dexamethasone, and the HMG 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, naltrindole significantly decreased tumor cell volumes using human MM cell xenografts in SCID mice. We hypothesize that naltrindole inhibits proliferation of MM cells through a non-opioid receptor-dependent mechanism.
- Received March 9, 2012.
- Revision received April 19, 2012.
- Accepted April 20, 2012.
- The American Society for Pharmacology and Experimental Therapeutics