The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo

Tumber, Anthony; Collins, Laura S.; Petersen, Kamille Dumong; Thougaard, Annemette; Christiansen, Sanne; Dejligbjerg, Marielle; Jensen, Peter Buhl; Sehested, Maxwell; Ritchie, James W.A.

doi:10.1007/s00280-006-0374-7

Cited by 67 publications

(54 citation statements)

References 34 publications

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“…Furthermore, HDACIs increase the efficiency of several anticancer drugs that target the DNA (Kim et al, 2003;Hede et al, 2006;Glaser, 2007;Tumber et al, 2007). The study of Lin CT results clearly show that VPA not only exhibits synergistic cytotoxicity with cisplatin in all of the ovarian carcinoma cells tested, but also can resensitize the cells that have acquired resistance to cisplatin.…”

Section: 3977 Valproic Acid Effects On Proliferation Apoptosis Angmentioning

confidence: 99%

Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo

Song¹,

Rong²,

Geng³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Inhibitors of histone deacetylase activity are emerging as a potentially important new class of anticancer agents. In this study, we assessed the anticancer effects of valproic acid (VPA) on ovarian cancer in vitro and in vivo. Cultured SKOV3 cells were treated by VPA with different concentrations and time, then the effects on cell growth, cell cycle, apoptosis, and related events were investigated. A human ovarian cancer model transplanted subcutaneously in nude mice was established, and the efficacy of VPA used alone and in combination with diammine dichloroplatinum (DDP) to inhibit the growth of tumors was also assessed. Proliferation of SKOV3 cells was inhibited by VPA in a dose and time dependent fashion. The cell cycle distribution changed one treatment with VPA, with decrease in the number of S-phase cells and increase in G1-phase. VPA could significantly inhibit the growth of the epithelial ovarian cancer SKOV3 cells in vivo without toxic side effects. Treatment with VPA combined with DDP demonstrated enhanced anticancer effects. The result of flow cytometry (FCM) indicated that after VPA in vitro and in vivo, the expression of E-cadherin was increased whereas vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were decreased. This study suggests that VPA could be a novel attractive agent for treatment of ovarian cancer.

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Section: 3977 Valproic Acid Effects On Proliferation Apoptosis Angmentioning

confidence: 99%

Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo

Song¹,

Rong²,

Geng³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Recent studies demonstrated that HDAC-Is can potentiate 5FU-induced inhibition of cell growth in colon and gastric cancer cells. 14,16 However, at least to our knowledge, our study is the first to demonstrate a synergistic effect of an HDAC-I such as vorinostat in combination with the pure inhibitor of TS RTX and with 5FU bio-modulated by FA (5FU-FA), the latter being the cornerstone of chemotherapy regimens in the colorectal cancer. We also provided evidences demonstrating that the mechanism of the synergistic interaction observed lay in the modulation of both TS and p53 protein expression.…”

Section: In Vitro Synergism Of Vorinostat Plus Ts-inhibitorsmentioning

confidence: 99%

“…4,9,13 Several reports, including microarray studies, have shown that the expression of the enzyme thymidilate synthase (TS) can be regulated by HDAC-Is. [14][15][16] In details, Glaser et al have shown that different HDAC-Is may control the expression of a "core" set of genes, eight upregulated and five downregulated, including TS, in several cell lines. 15 TS is an essential enzyme for the de novo synthesis of thymidilate (dTMP) and subsequently DNA synthesis, and is a critical target for 5FU and RTX.…”

Section: Introductionmentioning

confidence: 99%

Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or Raltitrexed

Gennaro¹,

Bruzzese²,

Pepe³

et al. 2009

Cancer Biology & Therapy

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Despite the introduction of several novel anticancer agents almost 50% of colorectal cancer (CRC) patients die for cancer suggesting the necessity of new therapeutical approaches. In this study we demonstrated that the HDAC inhibitor vorinostat exerted potent antiproliferative effect in a panel of mut-and wt-p53 human CRC cell lines. Moreover, in combination with 5-fluorouracil modulated by folinic acid (5FU-FA) or with Raltitrexed (RTX), both commonly used in the treatment of this disease, it showed a clear schedule-dependent synergistic antiproliferative interaction as demonstrated by calculating combination indexes. Only simultaneous, or 24 h pretreatment with vorinostat followed by either agent, produced synergistic effect paralleled by evident cell cycle perturbations with major S-phase arrest. Moreover, we provided for the first time evidences that vorinostat can overcome resistance to both 5FU and RTX. Downmodulation of Thymidilate synthase (TS) protein induced by vorinostat within 24 h, represented a key factor in enhancing the effects of both drugs in sensitive as well as resistant tumor cells. Furthermore, p53, whose wildtype expression is critical for sensitivity to 5FU and RTX, was upregulated by vorinostat in wt-and downregulated in mut-p53 cells, suggesting an additional mechanism of the antiproliferative synergistic interactions observed. Overall these data add new insights in the mechanism of vorinostat antitumor effect and suggested that the association of vorinostat plus 5FU-FA and/or RTX should be clinically explored.

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“…Since its approval a number of trials have been initiated to determine the efficacy of the combination of SAHA with existing chemotherapeutics for treatment of patients with progressive metastatic or unresectable colorectal cancer (clinicaltrials.gov), including combination with 5FU/LV and FOLFOX (5FU-Leucovorin/oxaliplatin). Preclinical studies have demonstrated that combination of HDACi with 5FU can synergistically enhance cell killing in vitro, and inhibit tumor growth in xenograft models, 144 establishing the potential of this approach. HDACi are also potent sensitizers to radiation therapy in multiple cell types, including colon cancer cells.…”

Section: Hdac Inhibitors In Clinical Trial For Colon Cancermentioning

confidence: 99%

HDACs and HDAC inhibitors in colon cancer

Mariadason¹

2008

Epigenetics

196

190

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The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo

Cited by 67 publications

References 34 publications

Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo

Effects of Valproic Acid on Proliferation, Apoptosis, Angiogenesis and Metastasis of Ovarian Cancer in Vitro and in Vivo

Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or Raltitrexed

HDACs and HDAC inhibitors in colon cancer

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