IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes

Abstract

Multidrug-resistant (MDR) multiple myeloma (MM) patients who fail chemotherapy frequently express MDR1 protein, which serves as an efflux pump that protects neoplastic cells. The expression of lung resistance protein (LRP), which mediates intercellular and nucleocytoplasmic transport, is also correlated with chemotherapy resistance and shorter survival of MM patients. Here, we investigated the chemotherapy-induced change of MDR expression in MM patients using quantitative RT-PCR. Overall expression levels of MDR1 and LRP in MM patients were significantly higher than those in control subjects and increased after chemotherapy. More than half of the patients exhibited increased expression of MDR1 (14/26) or LRP (17/26) after chemotherapy. Also, the expression of inhibitor of apoptosis proteins (IAP) was determined in association with the prognosis of the patients. Among patients with increased MDR1-expression after chemotherapy, those with a poor outcome exhibited significant increases in survivin, cIAP1, cIAP2, and XIAP expression by chemotherapy compared with those with a good prognosis. Similarly, in the LRP expression-increased group, patients with a poor outcome showed significant increases of cIAP1 and cIAP2 expression compared with those with longer survival. In patients with reduced-MDR1 or LRP expression after chemotherapy, changes in the expression of IAPs induced by chemotherapy did not correlate with their prognosis. These findings indicate that IAP family proteins might play a role in worsening the prognosis of MM patients in association with chemotherapy-induced overexpression of MDR1 or LRP. Am. J. Hematol. 81:824-831, 2006. V V C 2006 Wiley-Liss, Inc.

Significant impact of survivin on myeloma cell growth

“…Growing evidence has indicated that survivin expression plays an essential role in drug resistance (reviewed Li 3 ). Our data and Nakagawa's report 30 underline this finding in MM and raise the hypothesis that inhibiting survivin may improve MM treatment.…”

“…In line with our results, a recent report indicates that the expression ratios for survivin were significantly higher in MM patients with poorer outcome, especially after chemotherapy. 30 Although a larger cohort of patients would be necessary to confirm our results (as soon as a reliable survivin mAb for flow cytometry analysis becomes available), our results strongly argue for survivin participation in myeloma progression. However, it would be of particular interest to study survivin involvement in the first steps of oncogenesis in MM.…”

The Effect of Survivin on Multidrug Resistance Mediated by P-Glycoprotein in MCF-7 and Its Adriamycin Resistant Cells

“…Although the correlation between Pgp and survivin expression is still debated in drug resistance, the overexpression of Pgp together with the upregulation of survivin was determined in association with the poor prognosis of the patients. 25) In our report, the mRNA expression of survivin was significantly suppressed after the Pgp was inhibited by its specific inhibitor verapamil. Verapamil, a calcium channel blocker, inhibits the efflux function of Pgp and cytoskeletal transfer and therefore plays an important role in circumvention of native and acquired chemoresistance of cancer cells.…”

OSU-03012, a Novel Celecoxib Derivative, Is Cytotoxic to Myeloma Cells and Acts through Multiple Mechanisms

“…Increased expression of the IAP family proteins, including XIAP and survivin, correlate with poor outcome and chemotherapy-induced drug resistance in MM (46). The mechanism by which XIAP and survivin are reduced by OSU-03012 remains uncertain, although it is known that Akt activates these prosurvival genes (47,48).…”