%0 Journal Article
%T Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma
%A Qian Zhou
%A Chi Hang Wong
%A Cecilia Pik Yuk Lau
%A Connie Wun Chun Hui
%A Vivian Wai Yan Lui
%A Stephen Lam Chan
%A Winnie Yeo
%J International Journal of Hepatology
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/103830
%X Mammalian target of rapamycin (mTOR) and the microtubules are shown to be potential targets for treating hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we evaluated the antitumor activity by cotargeting of the mTOR (using allosteric mTOR inhibitor everolimus) and the microtubules (using novel microtubule-stabilizing agent patupilone) in HCC models. In vitro studies showed that either targeting mTOR signaling with everolimus or targeting microtubules with patupilone was able to suppress HCC cell growth in a dose-dependent manner. Cotargeting of the mTOR (by everolimus) and the microtubules (by patupilone, at low nM) resulted in enhanced growth inhibition in HCC cells (achieving maximal growth inhibition of 60¨C87%), demonstrating potent antitumor activity of this combination. In vivo studies showed that everolimus treatment alone for two weeks was able to inhibit the growth of Hep3B xenografts. Strikingly, the everolimus/patupilone combination induced a more significant antitumor activity. Mechanistic study demonstrated that this enhanced antitumor effect was accompanied by marked cell apoptosis induction and antiangiogenic activity, which were more significant than single-agent treatments. Our findings demonstrated that the everolimus/patupilone combination, which had potent antitumor activity, was a potential therapeutic strategy for HCC. 1. Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide [1, 2]. Surgical resection and liver transplantation are the two mainstays of curative treatment for HCC, but can only be applied to the early stage of HCC [3, 4]. The majority of patients with HCC are not amenable to, or eventually failed, locoregional therapies and have to be considered for systemic treatment. Although sorafenib (a multikinase inhibitor of VEGFR, PDGFR, and Raf) has been approved for the treatment of HCC as the first-line therapy for unresectable HCC, the outlook of patients with advanced disease remains dismal [5, 6]. These reasons exemplify the need to design more effective therapeutic strategies. Everolimus (RAD001, Afinitor), a rapamycin analogue, is an oral mammalian target of rapamycin (mTOR) inhibitor. mTOR is a key effector in the PI3K/Akt/mTOR pathway and it plays a critical role in regulating cell proliferation, survival, and angiogenesis [7]. Everolimus has been approved for the treatment of papillary renal carcinoma, pancreatic neuroendocrine tumor, some types of breast cancer, and subependymal giant cell
%U http://www.hindawi.com/journals/ijh/2013/103830/