Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol Journal Article
| Authors: | Solit, D. B.; Basso, A. D.; Olshen, A. B.; Scher, H. I.; Rosen, N. |
| Article Title: | Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol |
| Abstract: | The phosphatidylinositol 3′-kinase/Akt pathway is activated frequently in human cancer, and has been implicated in tumor proliferation, cell survival, and resistance to apoptotic stimuli. Akt forms a complex with heat shock protein (Hsp) 90 and Cdc37, and inhibitors of Hsp90 cause Akt degradation. 17-allylamino-17-demethoxygeldanamycin (17-AGG) is an Hsp90 inhibitor currently in Phase I clinical trial. 17-AAG inhibits Akt activation and expression in tumors, and has antitumor activity in breast cancer xenografts. The combination of 17-AAG and Taxol is synergistic, and 17-AAG sensitizes tumor cells to Taxol-induced apoptosis in a schedule-dependent manner. Transfection of membrane-bound p110 PI3k prevented 17-AAG inactivation of Akt and abrogated the enhancement of Taxol-induced apoptosis caused by the drug. 17-AAG and Taxol could be administered together at their maximally tolerated doses to tumor-bearing mice. Doses of 17-AAG that induce HER2 degradation and cause Akt inactivation but have no single agent activity were effective in sensitizing tumors to Taxol. Enhancement was schedule-dependent and maximal when Taxol and 17-AAG were administered on the same day. These results suggest that Hsp90 inhibitors can effectively suppress Akt activity in animal models of human cancer at nontoxic doses, thus sensitizing tumor cells to proapoptotic stimuli. |
| Keywords: | protein kinase b; controlled study; protein expression; unclassified drug; human cell; proto-oncogene proteins; clinical trial; drug potentiation; nonhuman; paclitaxel; protein function; cell proliferation; cell cycle protein; animal cell; animals; mice; animal tissue; cell survival; cell division; apoptosis; controlled clinical trial; breast cancer; protein degradation; drug administration schedule; animal experiment; animal model; down-regulation; antineoplastic activity; cancer cell culture; enzyme activation; tumor xenograft; dose-response relationship, drug; xenograft model antitumor assays; breast neoplasms; phosphatidylinositol 3 kinase; drug synergism; genetic transfection; protein-serine-threonine kinases; proto-oncogene proteins c-akt; tumor cell; heat shock protein 90; hsp90 heat-shock proteins; down regulation; receptor, erbb-2; maximum tolerated dose; phase 1 clinical trial; m protein; protein inhibitor; benzoquinones; lactams, macrocyclic; rifabutin; oncogene neu; drug sensitization; 17 allylamino 17 demethoxygeldanamycin; humans; human; female; priority journal; article; protein p110 p13k |
| Journal Title: | Cancer Research |
| Volume: | 63 |
| Issue: | 9 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2003-05-01 |
| Start Page: | 2139 |
| End Page: | 2144 |
| Language: | English |
| PUBMED: | 12727831 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
