Abstract 4903: D-alpha-tocopheryl polyethylene glycol succinate (TPGS) induces apoptosis and cell cycle arrest selectively in breast cancer cells by targeting aberrantly activated pathways engaging survivin signaling
Authors: Neophytou Christiana M. , Constantinou Constantina , Constantinou Andreas I. 
Published: August 2012

Abstract
D-alpha-tocopheryl polyethylene glycol succinate (TPGS) is a water-soluble derivative of natural vitamin E, formed by the esterification of vitamin E succinate with polyethylene glycol (PEG). TPGS is finding applications in nanoparticle formulations where it acts as an emulsifier and serves as a promising vehicle for the delivery of anticancer drugs with poor water solubility, bioavailability and cellular uptake. Furthermore, TPGS inhibited the growth of human prostate and lung carcinoma cells both in vitro and in vivo by promoting apoptosis. The objectives of the present study were to: a) determine if there are differences between normal and cancer cells in response to TPGS treatment and b) to elucidate the pathways leading to apoptosis. For this purpose we used multiple breast cancer cell lines as well as normal immortalized breast cells, in order to assess the ability of TPGS to induce cell death. In addition, we thoroughly investigated the mechanism of cell death induction in MDA-MB-231 cells and in MCF-7 cells. The results of our study clearly show that TPGS can effectively decrease cancer cell number by triggering apoptotic signaling pathways as well as by inducing G1-phase cell cycle arrest. In marked contrast, the cell number of “normal” immortalized MCF-10A and MCF-12F cell lines was not significantly affected by TPGS treatment. The decreased levels of full length PARP, in the presence and absence of the 89 kDa product, suggests that TPGS triggered both caspase -dependent and -independent pathways of programmed cell death, depending on the tissue context. Furthermore, we observed a decrease in the Bcl-2/Bax ratio and release of AIF and Endo G from the mitochondria to the cytoplasm in MCF-7 cells suggesting that these effectors are involved in the induction of caspase-independent apoptosis. The selective chemotherapeutic effects of TPGS may possibly be attributed to down regulation of the anti-apoptotic proteins Survivin and Bcl-2 that are overexpressed in most cancer cells. The inhibition of cell proliferation at G1 observed in MCF-7 and MDA-MB-231 cells may also relate to the two-fold decrease in Survivin mRNA and subsequent elimination of Survivin protein levels. In conclusion, our results show clearly that TPGS is selectively cytotoxic to cancer cells and suggest that this vitamin E derivative, in combination with other drugs, may be useful in the treatment of tumors that are resistant to caspase-activating therapeutic agents. The current use of TPGS as a vehicle for the delivery of anticancer drugs, and the insights gained from this study regarding its mode of apoptotic action provides unsurpassed opportunities for the “combination” cancer chemotherapy approach.
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 4903. doi:1538-7445.AM2012-4903