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Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models
Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histo...
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Published in: | Molecular cancer therapeutics 2009-02, Vol.8 (2), p.342-349 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains
incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing
the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to
determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase
inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines
were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat
and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment
with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7
activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and
in the number of cells arrested in the G 2 -M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead
to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs,
it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat
and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing
a rational basis for the clinical use of this combination for the treatment of colorectal cancer. [Mol Cancer Ther 2009;8(2):342–9] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-08-0534 |