Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models

Abstract

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]

Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms

“…In the present study, the co-administration of VPA with PI, MG132, PI-1 or PR-39 induced a marked increase in apoptosis in human colorectal cancer cells. Our results are consistent with those reported by other groups using several different cell systems and various combinations of HDACIs and PIs (1,15,22,35,39).…”

“…In cell culture models, HDAC inhibitors (HDACIs) have been shown to decrease proliferation rates, induce apoptosis and induce autophagy-related cell death in several cancer cell lines. Due to their relative specificity toward cancer cells, HDACIs represent a new class of cancer treatment agents that are generally well tolerated (1).…”

“…The rationale to targeting the proteasome in cancer arises from evidence that indicates that malignant cells accumulate misfolded/damaged proteins, which are disposed of by the proteasome, suggesting that tumor cells have a stronger dependency on proteasome activity compared to that of normal Valproic acid, an anti-epileptic drug and a histone deacetylase inhibitor, in combination with proteasome inhibitors exerts antiproliferative, pro-apoptotic and chemosensitizing effects in human colorectal cancer cells: Underlying molecular mechanisms MOHAMED-SALAH I. ABAZA 1 , ABDUL-MAJEED BAHMAN 1 and RAJA'A J. AL-ATTIYAH cells (6). The 26S proteasome is the primary subcellular component of the protein degradation pathway that regulates the turnover of proteins involved in cell cycle progression and apoptosis, such as the p21 cyclin-dependent kinase (CDK) inhibitor (CDKI), cyclins and IκB, a regulator of nuclear factor-κB (NFκB) transcriptional activity.…”

Increased proteasome subunit protein expression and proteasome activity in colon cancer relate to an enhanced activation of nuclear factor E2-related factor 2 (Nrf2)

“…Under such stress conditions, that is, during inflammation, the expression of proteasome proteins might be enhanced in a Nrf2-dependent manner, accounting for increased proteasome activity and UPP-mediated survival and growth of colon cancer cells. In line with this notion, very recent studies revealed that proteasome inhibition or knockdown of certain proteasomal subunit proteins impair the growth and survival of colorectal cancer cells (Chen et al, 2009;Pitts et al, 2009). Nuclear factor E2-related factor 2 (Nrf2)-induced S5a and a-5 expression in colon epithelial cells confers protection from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.…”

“…Accordingly, proteasome inhibition has meanwhile become a valuable and powerful tool in the treatment of certain types of cancer (Almond and Cohen, 2003;Goy et al, 2003;Adams, 2004); yet, other tumor entities turned out to be rather resistant to proteasome inhibitors. Nevertheless, recent studies (Chen et al, 2009;Pitts et al, 2009) showed that proteasome inhibition might also be effective for the treatment of colon cancer.…”