Abstract

Arsenic Trioxide (ATO) is highly active in acute promyelocytic leukemia (APL) and has activity in several other diseases including multiple myeloma. Since arsenicals are active and it is known that organic arsenicals are less toxic than ATO, the testing of new organic arsenicals is warranted. One such compound, ZIO-101 is in phase I/II studies. Therefore we previously compared the ability of ZIO-101 and ATO to kill four myeloma cell lines (RPMI 8226, U266, KMS11, MM.1s) that display differential sensitivity to ATO. Sensitivity to ATO and ZIO-101 did not correlate, as the most ATO resistant line (RPMI 8226) was highly sensitive to ZIO-101. We and others have reported that glutathione (GSH) is a critical regulator of ATO-induced cell death and we have utilized ascorbic acid (AA) as a GSH depleting agent both in vitro as well as clinically. We therefore also tested the effects of GSH depletion on ZIO-101-induced cell death in MM cell lines. BSO was much more effective at sensitizing cells to ATO than to ZIO-101. Moreover while AA could sensitize cells to ATO, it actually protected cells from cell death induced by ZIO-101. Taken together these data suggest ZIO-101 is active against myeloma cells although factors that determine the potency of this compound are different than those for ATO. To better characterize these differences gene expression profiling of the cellular response to ZIO-101 was performed. RNA was isolated from the 4 cell lines treated with ZIO-101 for 0, 6 and 24 h and profiling performed using Affymetrix Hu133 plus 2 arrays. We initially focused on genes that demonstrated similar changes in all four cell lines. 320 probes demonstrated an increase of 1.5 or greater at 6 h while only 58 increased at 24 h. Additionally 265 genes were decreased by at least 1.5 fold at 6 h while only 12 genes were down regulated 1.5 or greater at 24 h. Interestingly the pattern of gene expression was distinct from that observed in similar experiments with ATO. Most notably genes associated with metal responses (MT-1, ZnT-1) and oxidative stress responses (increased expression of HO-1, NQO-1, malic enzyme, GSH synthesis pathway, ferritin) were either absent or only transiently increased. In contrast there was increased expression of the pro-apoptotic gene Noxa compared to ATO treatment in the 4 cell lines. Taken together these data indicate the cellular response to ZIO-101 does not include the up regulation of protective pathways and suggest that ZIO-101 does not initiate cell death through the induction of oxidative stress. This may reflect differences in either metabolism or mechanism of action. Thus resistance to one form of arsenic does not preclude use of another. A phase I/II study of ZIO-101 in myeloma is underway.

Disclosures: Robert Gale is the Vice President of Research for ZIOPHARM Oncology which is developing ZIO-101.; Robert Gale.

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