Abstract 4777: The role of BAG3 in human leukemia cells’ response to the experimental anticancer drug laromustine

Abstract

Abstract The experimental anticancer drug laromustine, which demonstrates moderate clinical efficacy against acute myelogenous leukemia and glioblastoma multiforme, yields two reactive electrophiles in situ. Therapeutic cytotoxicity is principally due to a 2-chloroethylating species that can cause lethal DNA crosslinks. However, the second electrophile, methyl isocyanate, triggers acute toxicity in cultured cancer cells and synergizes with the cogenerated 2-chloroethylating activity. The mechanism by which laromustine kills cancer cells likely includes apoptosis. We measured changes in transcription for 88 genes relating to this cell death pathway cultured human promyelocytic (HL-60) cells using quantitative real-time reverse transcriptase PCR. Cultured cells were treated with drug for six hours before harvesting mRNA for analysis. Of these genes, the expression of BAG3, whose encoded protein is also known as CAIR-1 or Bis, was increased by more than 300 fold in cells exposed to laromustine. By forming a complex with heat shock protein 70 (Hsp70), it is thought that BAG3 promotes anti-apoptotic activity by interfering with protein chaperones and release of cytochrome-c. We are also examining effects on the entire transcriptome upon treatment with laromustine using GeneChip Microarrays. Finally, we have created a stable BAG3 knockdown cell line using an shRNA construct via lentiviral transfection. Substantial differences in laromustine-induced cytotoxicity in differing BAG3 backgrounds would suggest a mechanistic role in a cell's defense against laromustine and possibly an improved clinical approach. Citation Format: Kevin P. Rice, Amanda J. Loya, Kayla M. Gross. The role of BAG3 in human leukemia cells’ response to the experimental anticancer drug laromustine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4777.