Naltrindole Inhibits Human Multiple Myeloma Cell Proliferation In Vitro and in a Murine Xenograft Model In Vivo

Abstract

It has been demonstrated previously that immune cell activation and proliferation were sensitive to the effects of naltrindole, a nonpeptidic ␦-opioid receptor-selective antagonist; therefore, we hypothesized that human multiple myeloma (MM) would be a valuable model for studying potential antineoplastic properties of naltrindole. [3 H]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 cultured human U266 MM cells in a time-and dose-dependent manner with an EC 50 of 16 M. The naltrindole-induced inhibition of U266 cell proliferation was not blocked by a 10-fold molar excess of naltrexone, a nonselective opioid antagonist. Additive inhibition of MM cell proliferation was observed when using a combination of naltrindole with the histone deacetylase 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, extracellular signal-regulated kinase and Akt, which may be related to its antiproliferative activity. The antiproliferative activity of naltrindole toward MM cells was maintained in cocultures of MM and bone marrow-derived stromal cells, mimicking the bone marrow microenvironment. In vivo, naltrindole significantly decreased tumor cell volumes in human MM cell xenografts in severe combined immunodeficient mice. We hypothesize that naltrindole inhibits the proliferation of MM cells through a nonopioid receptor-dependent mechanism.

Knockdown of microtubule actin crosslinking factor 1 inhibits cell proliferation in MC3T3-E1 osteoblastic cells

“…The cell proliferation and viability was detected using Vi-Cell XR cell viability analyzer (Beckman Coulter, USA) as previously described (26 , 27) . This technique detects the cell number and cell viability by applying trypan blue dye-exclusion staining combined with image-based data analysis.…”

Identification of an irreversible PPARγ antagonist with potent anticancer activity

“…Previously, employing pharmacophore‐based molecular modeling, we have rationally designed and synthesized series of trisubstituted triazoles as novel delta opioid receptor ligands 6,7 . More recently, we reported that NTI inhibited the growth of human U266 cancer cells in vitro and in vivo in a mouse xenograft model, by an opioid receptor independent mechanism 5 . Consequently, several of the triazole analogs, including MM902, were tested for their effects on the growth of human U266 cells.…”

“…Previously, we reported that naltrindole (NTI), a selective delta opioid receptor antagonist, inhibited human multiple myeloma cell growth in vitro (EC 50 = 18.5 μmol/L) and exhibited efficacy in a mouse xenograft model, by interaction with non-opioid receptor targets. 5 Employing pharmacophore-based molecular modeling of NTI analogs, we have rationally designed and synthesized a series of trisubstituted triazoles as new delta opioid receptor ligands, 6,7 which in turn have led to the discovery of a novel compound MM902 l showing no appreciable binding affinity to opioid receptors ( Figure 1).…”

“…vitro and in vivo in a mouse xenograft model, by an opioid receptor independent mechanism 5. Consequently, several of the triazole analogs, including MM902, were tested for their effects on the growth of human U266 cells.…”

Crosstalk between Delta Opioid Receptor and Nerve Growth Factor Signaling Modulates Neuroprotection and Differentiation in Rodent Cell Models

“…Naltrindole inhibited the increase in phosphorylation of MAPK by DADLE in PC12h cells ( Figure 7 ) and that of both Akt and MAPK in F11 cells ( Figure 6 ), indicating that DADLE may act through the Oprd1 to induce its effect. We observed that F11 cells did not survive in 100 μM of naltrindole for 24 h. This is most likely because high concentration of naltrindole blocked the basal survival PI3K/Akt signaling [ 8 , 46 ], resulting in apoptotic death of F11 cells. To see if the increase in Akt phosphorylation after 24 h of DADLE treatment on F11 cells differentiated in the presence of NGF is specific to the presence of NGF, the cells were treated with 100 nM K252a before adding DADLE for 24 h of treatment.…”