Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death
Multitarget compounds that act on a diverse set of regulatory pathways are emerging as a therapeutic approach for a variety of cancers. Toward a more specified use of this approach, we hypothesize that the desired efficacy can be recreated in terms of a particular combination of relatively more spec...
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2011
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| Online Access: | http://hdl.handle.net/1721.1/67045 https://orcid.org/0000-0002-1801-5548 |
| _version_ | 1811072752866557952 |
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| author | Wands, Jack R. Cosgrove, Benjamin D. Hemann, Michael Pritchard, Justin R. Griffith, Linda G Lauffenburger, Douglas A |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Wands, Jack R. Cosgrove, Benjamin D. Hemann, Michael Pritchard, Justin R. Griffith, Linda G Lauffenburger, Douglas A |
| author_sort | Wands, Jack R. |
| collection | MIT |
| description | Multitarget compounds that act on a diverse set of regulatory pathways are emerging as a therapeutic approach for a variety of cancers. Toward a more specified use of this approach, we hypothesize that the desired efficacy can be recreated in terms of a particular combination of relatively more specific (i.e., ostensibly single target) compounds. We test this hypothesis for the geldanamycin analogue 17-Allylamino-17-demethoxygeldanamycin (17AAG) in hepatocellular carcinoma cells, measuring critical phosphorylation levels that indicate the kinase pathway effects correlating with apoptotic responsiveness of the Hep3B cell line in contrast to the apoptotic resistance of the Huh7 cell line. A principal components analysis (PCA) constructed from time course measurements of seven phosphoprotein signaling levels identified modulation of the AKT, IκB kinase, and signal transducer and activator of transcription 3 pathways by 17AAG treatment as most important for distinguishing these cell-specific death responses. The analysis correctly suggested from 17AAG-induced effects on these phosphoprotein levels that the FOCUS cell line would show apoptotic responsiveness similarly to Hep3B. The PCA also guided the inhibition of three critical pathways and rendered Huh7 cells responsive to 17AAG. Strikingly, in all three hepatocellular carcinoma lines, the three-inhibitor combination alone exhibited similar or greater efficacy to 17AAG. We conclude that (a) the PCA captures and clusters the multipathway phosphoprotein time courses with respect to their 17AAG-induced apoptotic responsiveness and (b) we can recreate, in a more specified manner, the cellular responses of a prospective multitarget cancer therapeutic. |
| first_indexed | 2024-09-23T09:11:47Z |
| format | Article |
| id | mit-1721.1/67045 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:11:47Z |
| publishDate | 2011 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/670452022-09-26T11:01:53Z Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death Wands, Jack R. Cosgrove, Benjamin D. Hemann, Michael Pritchard, Justin R. Griffith, Linda G Lauffenburger, Douglas A Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Lauffenburger, Douglas A. Pritchard, Justin Robert Cosgrove, Benjamin D. Hemann, Michael Griffith, Linda G. Lauffenburger, Douglas A. Multitarget compounds that act on a diverse set of regulatory pathways are emerging as a therapeutic approach for a variety of cancers. Toward a more specified use of this approach, we hypothesize that the desired efficacy can be recreated in terms of a particular combination of relatively more specific (i.e., ostensibly single target) compounds. We test this hypothesis for the geldanamycin analogue 17-Allylamino-17-demethoxygeldanamycin (17AAG) in hepatocellular carcinoma cells, measuring critical phosphorylation levels that indicate the kinase pathway effects correlating with apoptotic responsiveness of the Hep3B cell line in contrast to the apoptotic resistance of the Huh7 cell line. A principal components analysis (PCA) constructed from time course measurements of seven phosphoprotein signaling levels identified modulation of the AKT, IκB kinase, and signal transducer and activator of transcription 3 pathways by 17AAG treatment as most important for distinguishing these cell-specific death responses. The analysis correctly suggested from 17AAG-induced effects on these phosphoprotein levels that the FOCUS cell line would show apoptotic responsiveness similarly to Hep3B. The PCA also guided the inhibition of three critical pathways and rendered Huh7 cells responsive to 17AAG. Strikingly, in all three hepatocellular carcinoma lines, the three-inhibitor combination alone exhibited similar or greater efficacy to 17AAG. We conclude that (a) the PCA captures and clusters the multipathway phosphoprotein time courses with respect to their 17AAG-induced apoptotic responsiveness and (b) we can recreate, in a more specified manner, the cellular responses of a prospective multitarget cancer therapeutic. National Institute of General Medical Sciences (U.S.). Cell Decision Processes Center National Cancer Institute (U.S.). Integrative Cancer Biology Program Massachusetts Institute of Technology. Presidential Fellowship National Institutes of Health (U.S.) 2011-11-16T22:45:55Z 2011-11-16T22:45:55Z 2009-08 2009-04 Article http://purl.org/eprint/type/JournalArticle 1538-8514 1535-7163 http://hdl.handle.net/1721.1/67045 Pritchard, J. R. et al. “Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death.” Molecular Cancer Therapeutics 8 (2009): 2183-2192. Web. 16 Nov. 2011. © 2011 American Association for Cancer Research https://orcid.org/0000-0002-1801-5548 en_US http://dx.doi.org/10.1158/1535-7163.MCT-08-1203 Molecular Cancer Therapeutics Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf American Association for Cancer Research PubMed Central |
| spellingShingle | Wands, Jack R. Cosgrove, Benjamin D. Hemann, Michael Pritchard, Justin R. Griffith, Linda G Lauffenburger, Douglas A Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| title | Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| title_full | Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| title_fullStr | Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| title_full_unstemmed | Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| title_short | Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| title_sort | three kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death |
| url | http://hdl.handle.net/1721.1/67045 https://orcid.org/0000-0002-1801-5548 |
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