Abstract
Abstract Laromustine is an experimental anticancer drug that has been tested in the clinic against acute myelogenous leukemia and glioblastoma multiforme. In the body, Laromustine's cytotoxic effects are a result of two cogenerated electrophiles, a 2-chloroethylating species that can cause lethal DNA damage and methylisocyanate, which carbamoylates sulfydryl groups in proteins. The mechanism by which Laromustine kills cancer cells likely includes apoptosis. In order to further investigate this phenomenon, the extent to which Laromustine affects cultured human promyelocytic (HL-60) cells’ use of 88 genes relating to this cell death pathway was examined using quantitative real-time reverse transcriptase PCR. Cultured cells were treated with drug for six hours before harvesting mRNA for analysis. The expression of a subset of the tested genes emerged as significantly different in cells treated with Laromustine as compared to control cells. Included among these genes are: TNFRSF10D, TNFRSF17, CD40LG, TRAF4, and BAG3. The expression of BAG3, whose encoded protein is also known as CAIR-1 or Bis, was increased by more than two orders of magnitude in HL-60 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 chaperoning and cytochrome-c release. It is possible that a pathway involving BAG3 could be a mechanism by which cells attempt to counter the effects of Laromustine exposure. Other apoptotic markers are also reported, including activation of caspase-3 and caspase-7, cleavage of poly(ADP-ribose) polymerase, and staining of annexin V. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1764. doi:1538-7445.AM2012-1764
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