Visit our Expo - Redox and Inflammation signaling 2012

The immunomodulator AS101 induces growth arrest and apoptosis in Multiple
Myeloma cells via the PI3-K/Akt pathway.
Michal Hayun1, Merav Weil1, Yaniv Naor1, Yona Kalechman1, Michael Albeck2,
Nechama Haran-Ghera3 and Benjamin Sredni1
1Safdié Institute for AIDS and Immunology Research, Faculty of Life Sciences,
2Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel; 3Department of
Immunology, The Weizman Institute of Science, Rehovot, Israel
Multiple Myeloma (MM) is a clonal B-cell malignancy affecting both the immune and the
skeletal systems, and accounts for 10% of all hematological cancers. The immunomodulator
ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) is a non toxic compound which
has been shown to have direct anti-tumoral properties in several tumor models. The present
study examined the anti-tumoral activity of AS101 compound by targeting certain signaling
pathway (PI3-K/Akt) crucial for survival of MM cells. We showed that AS101 induced a
significant inhibition of cell proliferation in MM cells which was time-and dose-dependent.
AS101 induced G2/M arrest, an effect associated with an increase of the p53 tumor
suppressor gene, cyclin-dependent kinase inhibitor p21WAF1, and CDK1 phosphorylation.
Longer incubation of MM cells with AS101 resulted in an increase in the early apoptotic cell
population and caspase 9 activity. PI3-K/Akt pathway is of particular interest because of its
role in inhibiting apoptosis and promoting cell proliferation. Downregulation of Akt, decrease
in Survivin expression and suppression of the antiapoptotic effect of exogenously addition of
IGF-1 were observed following AS101 treatment. AS101 was also found to sinergize with
Rapamycin in inducing G2/M arrest in MM cells. Rapamycin is a selective inhibitor of the
phosphoprotein mammalian target of rapamycin (mTOR), a downstream target of pAkt. Our
results indicate that the immunomodulator AS101, currently being used in clinical studies
alone or combined with Rapamycin may be effective in the treatment of MM patients.
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