Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma
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 allos...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2013-01-01
|
| Series: | International Journal of Hepatology |
| Online Access: | http://dx.doi.org/10.1155/2013/103830 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850162338468986880 |
|---|---|
| author | Qian Zhou Chi Hang Wong Cecilia Pik Yuk Lau Connie Wun Chun Hui Vivian Wai Yan Lui Stephen Lam Chan Winnie Yeo |
| author_facet | Qian Zhou Chi Hang Wong Cecilia Pik Yuk Lau Connie Wun Chun Hui Vivian Wai Yan Lui Stephen Lam Chan Winnie Yeo |
| author_sort | Qian Zhou |
| collection | DOAJ |
| description | 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 60–87%), 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. |
| format | Article |
| id | doaj-art-f7bc6b79d3a2498fa0b26784ca91b621 |
| institution | OA Journals |
| issn | 2090-3448 2090-3456 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Hepatology |
| spelling | doaj-art-f7bc6b79d3a2498fa0b26784ca91b6212025-08-20T02:22:36ZengWileyInternational Journal of Hepatology2090-34482090-34562013-01-01201310.1155/2013/103830103830Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular CarcinomaQian Zhou0Chi Hang Wong1Cecilia Pik Yuk Lau2Connie Wun Chun Hui3Vivian Wai Yan Lui4Stephen Lam Chan5Winnie Yeo6Department of Clinical Oncology, The Chinese University of Hong Kong, Hong KongDepartment of Clinical Oncology, The Chinese University of Hong Kong, Hong KongCancer Drug Testing Unit, State Key Laboratory of Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong KongCancer Drug Testing Unit, State Key Laboratory of Oncology in South China, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong KongDepartment of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USADepartment of Clinical Oncology, The Chinese University of Hong Kong, Hong KongDepartment of Clinical Oncology, The Chinese University of Hong Kong, Hong KongMammalian 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 60–87%), 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.http://dx.doi.org/10.1155/2013/103830 |
| spellingShingle | Qian Zhou Chi Hang Wong Cecilia Pik Yuk Lau Connie Wun Chun Hui Vivian Wai Yan Lui Stephen Lam Chan Winnie Yeo Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma International Journal of Hepatology |
| title | Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma |
| title_full | Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma |
| title_fullStr | Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma |
| title_full_unstemmed | Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma |
| title_short | Enhanced Antitumor Activity with Combining Effect of mTOR Inhibition and Microtubule Stabilization in Hepatocellular Carcinoma |
| title_sort | enhanced antitumor activity with combining effect of mtor inhibition and microtubule stabilization in hepatocellular carcinoma |
| url | http://dx.doi.org/10.1155/2013/103830 |
| work_keys_str_mv | AT qianzhou enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma AT chihangwong enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma AT ceciliapikyuklau enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma AT conniewunchunhui enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma AT vivianwaiyanlui enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma AT stephenlamchan enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma AT winnieyeo enhancedantitumoractivitywithcombiningeffectofmtorinhibitionandmicrotubulestabilizationinhepatocellularcarcinoma |