File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1016/j.bcp.2012.01.013
- Scopus: eid_2-s2.0-84858077469
- PMID: 22285225
- WOS: WOS:000301906900003
- Find via
Supplementary
- Citations:
- Appears in Collections:
Article: Sustained antitumor activity by co-targeting mTOR and the microtubule with temsirolimus/vinblastine combination in hepatocellular carcinoma
Title | Sustained antitumor activity by co-targeting mTOR and the microtubule with temsirolimus/vinblastine combination in hepatocellular carcinoma |
---|---|
Authors | |
Keywords | Anti-apoptotic/survival proteins Hepatocellular carcinoma Microtubule mTOR Sustained antitumor activity |
Issue Date | 2012 |
Citation | Biochemical Pharmacology, 2012, v. 83 n. 9, p. 1146-1158 How to Cite? |
Abstract | The mammalian target of rapamycin (mTOR) and the microtubules are prominent druggable targets for hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we hypothesized that co-targeting of mTOR (by mTOR inhibitor temsirolimus) and the microtubule (by microtubule-destabilizing agent vinblastine) would be more efficacious than single targeting in HCC models. In vitro studies showed that effective inhibition of mTOR signaling with temsirolimus alone was able to suppress HCC cell growth in a dose-dependent manner. Among five cell lines tested, Huh7 was the most temsirolimus-sensitive (IC 50 = 1.27 ± 0.06 μM), while Hep3B was the most temsirolimus-resistant (IC 50 = 52.95 ± 17.14 μM). We found that co-targeting of mTOR (by temsirolimus) and the microtubule (by vinblastine, at low nM) resulted in marked growth inhibition in Huh7 cells and synergistic growth inhibition in Hep3B cells (achieving maximal growth inhibition of 80-90%), demonstrating potent antitumor activity of this novel combination. In vivo studies showed that temsirolimus treatment alone for 1 week was able to inhibit the growth of Huh7 xenografts. Strikingly, the temsirolimus/vinblastine combination induced a significant and sustained antitumor activity (up to 27 days post-treatment), with effective reduction of tumor vessel density in both Huh7 and Hep3B xenograft models. Mechanistic investigation revealed that this marked antitumor effect was accompanied by specific and concerted down-regulation of several key anti-apoptotic/survival proteins (survivin, Bcl-2, and Mcl-1), which was not observed in single agent treatments. Our findings demonstrated that the potent anti-cancer activity of this co-targeting strategy was indeed mediated in parts by inhibition of these key survival/anti-apoptotic proteins. © 2012 Elsevier Inc. |
Persistent Identifier | http://hdl.handle.net/10722/194350 |
ISSN | 2023 Impact Factor: 5.3 2023 SCImago Journal Rankings: 1.365 |
ISI Accession Number ID |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Zhou, Q | - |
dc.contributor.author | Lui, VWY | - |
dc.contributor.author | Lau, CPY | - |
dc.contributor.author | Cheng, SH | - |
dc.contributor.author | Ng, MHL | - |
dc.contributor.author | Cai, Y | - |
dc.contributor.author | Chan, SL | - |
dc.contributor.author | Yeo, W | - |
dc.date.accessioned | 2014-01-30T03:32:29Z | - |
dc.date.available | 2014-01-30T03:32:29Z | - |
dc.date.issued | 2012 | - |
dc.identifier.citation | Biochemical Pharmacology, 2012, v. 83 n. 9, p. 1146-1158 | - |
dc.identifier.issn | 0006-2952 | - |
dc.identifier.uri | http://hdl.handle.net/10722/194350 | - |
dc.description.abstract | The mammalian target of rapamycin (mTOR) and the microtubules are prominent druggable targets for hepatocellular carcinoma (HCC). PI3K/Akt/mTOR activation is associated with resistance to microtubule inhibitors. Here, we hypothesized that co-targeting of mTOR (by mTOR inhibitor temsirolimus) and the microtubule (by microtubule-destabilizing agent vinblastine) would be more efficacious than single targeting in HCC models. In vitro studies showed that effective inhibition of mTOR signaling with temsirolimus alone was able to suppress HCC cell growth in a dose-dependent manner. Among five cell lines tested, Huh7 was the most temsirolimus-sensitive (IC 50 = 1.27 ± 0.06 μM), while Hep3B was the most temsirolimus-resistant (IC 50 = 52.95 ± 17.14 μM). We found that co-targeting of mTOR (by temsirolimus) and the microtubule (by vinblastine, at low nM) resulted in marked growth inhibition in Huh7 cells and synergistic growth inhibition in Hep3B cells (achieving maximal growth inhibition of 80-90%), demonstrating potent antitumor activity of this novel combination. In vivo studies showed that temsirolimus treatment alone for 1 week was able to inhibit the growth of Huh7 xenografts. Strikingly, the temsirolimus/vinblastine combination induced a significant and sustained antitumor activity (up to 27 days post-treatment), with effective reduction of tumor vessel density in both Huh7 and Hep3B xenograft models. Mechanistic investigation revealed that this marked antitumor effect was accompanied by specific and concerted down-regulation of several key anti-apoptotic/survival proteins (survivin, Bcl-2, and Mcl-1), which was not observed in single agent treatments. Our findings demonstrated that the potent anti-cancer activity of this co-targeting strategy was indeed mediated in parts by inhibition of these key survival/anti-apoptotic proteins. © 2012 Elsevier Inc. | - |
dc.language | eng | - |
dc.relation.ispartof | Biochemical Pharmacology | - |
dc.subject | Anti-apoptotic/survival proteins | - |
dc.subject | Hepatocellular carcinoma | - |
dc.subject | Microtubule | - |
dc.subject | mTOR | - |
dc.subject | Sustained antitumor activity | - |
dc.title | Sustained antitumor activity by co-targeting mTOR and the microtubule with temsirolimus/vinblastine combination in hepatocellular carcinoma | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.bcp.2012.01.013 | - |
dc.identifier.pmid | 22285225 | - |
dc.identifier.scopus | eid_2-s2.0-84858077469 | - |
dc.identifier.volume | 83 | - |
dc.identifier.issue | 9 | - |
dc.identifier.spage | 1146 | - |
dc.identifier.epage | 1158 | - |
dc.identifier.isi | WOS:000301906900003 | - |
dc.identifier.issnl | 0006-2952 | - |