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Arsenic trioxide-mediated growth inhibition and apoptosis in multiple myeloma cells correlated with inhibition of nuclear factor -kappaB activity

Arsenic trioxide-mediated growth inhibition and apoptosis in multiple myeloma cells correlated with inhibition of nuclear factor -kappaB activity

Blood 98(11 Part 1): 100a-101a

ISSN/ISBN: 0006-4971

Promising results from recent clinical trials have renewed interest in evaluating arsenic-containing compounds as anticancer agents. Arsenic trioxide (As2O3) has been demonstrated to be an effective drug in the treatment of acute promyelocytic leukemia by inducing apoptosis in leukemic cells both in vitro and in vivo. We investigated the effect of As2O3 on proliferation and apoptosis in multiple myeloma (MM) cell-lines (VAD-1, U266, -U266/LR, RPMI8226, 8226/LR and NCI) and T-cell and B-cell leukemia cell-lines (NB-4, Molt-4 and H937) at pharmacological concentrations (1X10-8 to 1X10-5 M). First, we showed that As2O3 significantly inhibited the proliferation of all six MM cell-lines in a dose-dependent manner with an IC50 of approximately 5X10-6 M. In addition, As2O3 induced apoptosis in the MM cell-lines. Next, we treated MM cell-lines with this drug in combination with other chemotherapeutic agents. The combination of As2O3 at a non-cytotoxic concentration (5X10-7 M) with melphalan markedly increased the sensitivity of MM cells to cell killing. Specifically, melphalan was cytotoxic at a 10,000-fo1d lower concentration using the combination compared to treatment with the chemotherapeutic agent alone. In contrast, this enhancement of cell killing using the drug combinations at lower doses was not observed in leukemia cell-lines. To address the mechanism of the anti-proliferative and apoptosis-inducing effects of As2O3, we determined the basal activity of NF-kappaB in both leukemia and myeloma cell-lines using fluorescent assay analysis. It showed that there is markedly higher NF-kappaB activity in MM cell-lines than that observed in both T-cell and B-cell leukemia cell-lines. Western blot analysis demonstrated that the levels of the inhibitor of NF-kappaB, IkappaB, were increased in cell lines treated with As2O3. In addition, previous studies suggest that As2O3 has an anti-angiogenic effect, and MM tumor cells have been shown to secrete vascular endothelial growth factor (VEGF). We measured VEGF levels following As2O3 exposure (5X10-7 M). This treatment decreased the amount of VEGF in culture supernatants obtained from MM cell lines as determined by ELISA. These results show the cytotoxin effect of As2O3 on MM, and suggest that combining this drug with chemotherapy may lead to cytotoxic effects at markedly decreased doses of both As2O3 and melphalan. In addition, our results suggest that As2O3 may produce anti-myeloma effects both directly by inhibiting NF-kappaB activity and indirectly by suppressing angiogenesis.

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Accession: 034440522

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