effects of arsenic trioxide and zoledronic acid on malignant plasma cells derived from bone marrow cells of multiple myeloma patients

ABSTRACT

Multiple myeloma [MM] is a disease of plasma cells that has fatal consequences. New agents associated with molecular targets have prompted clinical investigators to design new treatment strategies initially for advanced MM and later for newly diagnosed MM, with encouraging preliminary results. We devised a project to assess the mechanisms of action of two drugs, Arsenic trioxide [ATO] and Zoledronic acid [Zometa] on Bone marrow mononuclear cells [BMMCs] derived from patients. Bone marrow samples were collected from 10 patients after receipt of formal consent. BMMCs were collected from samples. In two parallel sets of experiments, BMMCs were treated with 0.5, 2, 6 micro M ATO and 0.1, 10, 100 micro M Zometa, for 72 h. The following analyses were then performed on treated cells as compared to untreated cells [assumed as control] cytotoxicity using Micro culture tetrazolium test [MTT assay]; matrix metalloproteinase-2 zymography; comparative gene expression analysis of IL-6, vascular endothelial growth factor [VEGF] and intercellular adhesion molecule-1 [ICAM-l]. MTT assay showed significant proliferation inhibition in ATO high dose treatment [6 uM]. However, no significant inhibitory effect of Zometa was seen. Zymography analyses showed significant decrease in gelatinolytic activity in treated cells. Analyses of gene expression using Real-Time RT-PCR methodology showed significant decrease in IL-6, ICAM-1, and VEGF genes as normalized against Hypoxanthine phosphoribosyltransferase normalizer and as compared with untreated cells. Both ATO and Zometa could significantly decrease MM cells critical phenotype and genotype. This finding could support the hypothesis that ATO or Zometa could inhibit growth and metastasis of malignant cells