Abstract 5469: Dexamethasone interrupts paclitaxel-induced apoptosis in solid tumor cells
Authors: Marianna Zavodovskaya, Carrie Brachmann, Jorge DiMartino, Daniel Pierce
Journal: Cancer Research (2015)

Abstract Determinants of sensitivity and resistance to taxane-based therapy have long been sought. Drug efflux, microtubule dynamics, and especially apoptosis regulation all play roles in resistance. Here, we focus on the impact of concurrent steroid treatment on apoptosis regulation. Because Cremophor- and polysorbate 80-formulated taxanes can cause serious or fatal hypersensitivity reactions, patients are routinely premedicated with glucocorticoids. Albumin-formulated nab-paclitaxel, on the other hand, does not require premedications. We now report results that confirm and extend previous data showing dexamethasone (Dex) treatment can antagonize paclitaxel (Ptx) induced apoptosis. We interrogated a panel of 20 cell lines (8 triple negative breast cancer [TNBC], 6 pancreatic ductal adenocarcinoma [PDAC], and 6 non-small cell lung cancer [NSCLC]) using a kinetic Caspase3/7 activation assay. Eighteen of 20 lines express detectable levels of the glucocorticoid receptor (GR) protein. Strikingly, in 15 of these GR+ lines, Dex inhibits Ptx-induced apoptosis with median reductions of 75%, 28%, and 29% in NSCLC, PDAC, and TNBC lines respectively. In GR+ H1755 NSCLC cells, the EC50 of the Dex effect is 4 nM, a clinically relevant range. To further characterize the mechanism by which Dex interrupts Ptx-induced apoptosis, we compared the effects of Dex in GR+ H1755 and GR- H522 NSCLC cells. We found that Dex inhibits Ptx-induced activation of c-Jun-NH2-kinase (JNK), which functions in cellular stress responses and apoptosis, in H1755 cells. JNK pThr183/pTyr185 and c-Jun pSer73 are both present at high levels in untreated H1755 cells. Ptx further increases c-Jun pSer73 levels while Dex reduces constitutive and Ptx-induced c-Jun phosphorylation, and also downregulates c-Jun protein. In contrast, Dex does not affect levels of either phospho c-Jun or c-Jun protein in H522 cells. We also found that Dex up-regulates transcription of negative regulators of the MAPK signaling pathway including MAPK phosphatase 1 (MKP1) and steroid-and glucocorticoid-regulated kinase 1 (SGK1). Consistent with previous reports, Ptx treatment leads to downregulation of the BCL2 family proteins MCL1 and BCLXL, and an increase in the inactive pSer70 form of BCL2. Concurrent Dex treatment antagonizes these Ptx-induced changes in GR+ H1755 cells but not in GR- H522 cells. The observed dex-mediated reduction in apoptosis correlates with a decrease in cleaved Caspase 3 levels in ptx treated GR+ H1755 cells. In light of this evidence of antagonism between glucocorticoids and Ptx-induced apoptosis, we think it possible that reduced antitumor activity may be an under-appreciated risk of concurrent administration of these agents. Our data argue that in making treatment decisions, taxane formulations that do not require glucocorticoids and glucocorticoid-free regimens for management of nausea and emesis should be considered. Citation Format: Marianna Zavodovskaya, Carrie Brachmann, Jorge DiMartino, Daniel Pierce. Dexamethasone interrupts paclitaxel-induced apoptosis in solid tumor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5469. doi:10.1158/1538-7445.AM2015-5469