Abstract LB-277: Dynamic functional analysis of the response of cancer cell lines to the drug UNBS1450

Abstract

Abstract The analysis of the dynamics of cellular responses to drugs is currently bounded by inherent limitations of the methods most often used to assess levels of promoter activity and protein abundance or activation. The sensitivity of these assays is limited by the averaging of analyte over many cells, which can produce an average that is not accurately descriptive of the wide range of activities of members of the population examined. The ability of these assays to indicate the trajectory of the various responses is limited by a very infrequent sampling rate, frequently 2–4 time points spread over many hours. These limits are further exacerbated by populations of treated cells' inhomogeneity in the timing of their own response to the drugs. To improve the determination of the functional dynamics of cells' responses to drugs, PBS-Bio has developed technology that allows gathering data from living cells using fluorescent reporter technology. This technology allows measurements to be made serially on single populations of cells at the individual cell level, providing both high sensitivity in terms of when even a small fraction of the cells exhibit significant shifts of a particular activity, the rate of shift of cells in the population to this different activity and the ability to temporally order the timing of events relative to each other. Experimentation on two cell lines, A549 and PC3, using a variety of drugs that affect different cellular processes and a set of fluorescent reporters that provide information on a variety of cellular processes it was possible to show that the modified cardenolide drug, UNBS1450 (Unibioscreen), provoked a very early reduction in the expression of the MCL1 and MYC genes, followed by induction of a strong apoptotic response in both cell lines. As loss of MCL1 provoked by other means has been shown to be sufficient to induce apoptosis in both these lines, a very strong case can be made for UNBS1450's ability to provoke Mcl1 protein reduction as the drug's mode of apoptotic induction. This finding would also implicate Mcl1 as a useful biomarker of the possible efficacy of UNBS1450. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-277. doi:10.1158/1538-7445.AM2011-LB-277