Inhibition of homologous recombination with vorinostat synergistically enhances ganciclovir cytotoxicity

Ladd, Brendon; Ackroyd, Jeffrey J.; Hicks, J. Kevin; Canman, Christine E.; Flanagan, Sheryl A.; Shewach, Donna S.

doi:10.1016/j.dnarep.2013.10.008

Cited by 15 publications

(14 citation statements)

References 48 publications

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“…The comet assay and γ-H2AX foci experiments by Ladd et al have shown that HSV-TK/GCV can cause DNA double-stranded breaks [ 25 ], which are frequently irreversible and result in cell death [ 7 ]. Such DNA damage can increase levels of ATM (ataxia telangiectasia mutated) and ATR (ATM-Rad3-related), both of which induce phosphorylation of serine 15 on p53; this prevents the interaction of MDM2 with p53 and reduces p53 ubiquitination and degradation [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Exogenous p53 and ASPP2 expression enhances rAdV-TK/GCV-induced death in hepatocellular carcinoma cells lacking functional p53

et al. 2016

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Suicide gene therapy using herpes simplex virus-1 thymidine kinase (HSV-TK) in combination with ganciclovir (GCV) has emerged as a potential new method for treating cancer. We hypothesize that the efficacy of HSV-TK/GCV therapy is at least partially dependent on p53 status in hepatocellular carcinoma (HCC) patients. Using recombinant adenoviral vectors (rAdV), TK, p53, and ASPP2 were overexpressed individually and in combination in Hep3B (p53 null) and HepG2 (p53 wild-type) cell lines and in primary HCC tumor cells. p53 overexpression induced death in Hep3B cells, but not HepG2 cells. ASPP2 overexpression increased rAdV-TK/GCV-induced HepG2 cell death by interacting with endogenous p53. Similarly, ASPP2 reduced survival in rAdV-TK/GCV-treated primary HCC cells expressing p53 wild-type but not a p53 R249S mutant. Mutated p53 was unable to bind to ASPP2, suggesting that the increase in rAdV-TK/GCV-induced cell death resulting from ASPP2 overexpression was dependent on its interaction with p53. Additionally, γ-H2AX foci, ATM phosphorylation, Bax, and p21 expression increased in rAdV-TK/GCV-treated HepG2 cells as compared to Hep3B cells. This suggests that the combined use of HSV-TK, GCV, rAdV-p53 and rAdV-ASPP2 may improve therapeutic efficacy in HCC patients lacking functional p53.

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Section: Discussionmentioning

confidence: 99%

Exogenous p53 and ASPP2 expression enhances rAdV-TK/GCV-induced death in hepatocellular carcinoma cells lacking functional p53

et al. 2016

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“…HDACi’s have been shown to directly downregulate homologous recombination and non-homologous end-joining in many cancer cell lines [ 17 - 20 ]. For example, in prostate cells, treatment with HDACi downregulates the protein expression levels of BRCA1, RAD51 and DNA-PK, and the mRNA expression levels of ATM, BRCA1, BRCA2, RAD51 and XRCC4 [ 4 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor sodium butyrate suppresses DNA double strand break repair induced by etoposide more effectively in MCF-7 cells than in HEK293 cells

Sun

Liu

et al. 2015

BMC Biochem

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BackgroundHistone deacetylase inhibitors (HDACi’s) are emerging as promising anticancer drugs alone or in combination with chemotherapy or radiotherapy agents. Previous research suggests that HDACi’s have a high degree of selectivity for killing cancer cells, but little is known regarding the impact of different cellular contexts on HDACi treatment. It is likely that the molecular mechanisms of HDACi’s involve processes that depend on the chromatin template, such as DNA damage and repair. We sought to establish the connection between the HDACi sodium butyrate and DNA double-strand break (DSB) damage in human breast cancer MCF-7 and non-cancerous human embryonic kidney293 (HEK293) cells.ResultsSodium butyrate inhibited the proliferation of both HEK293 and MCF-7 cells in a dose- and time- dependent manner, but the effects on MCF-7 cells were more obvious. This differential effect on cell growth was not explained by differences in cell cycle arrest, as sodium butyrate caused an arrest in G1/G2 phase and a decrease in S phase for both cell lines. At high doses of sodium butyrate or in combination with etoposide, MCF-7 cells formed fewer colonies than HEK293 cells. Furthermore, sodium butyrate enhanced the formation of etoposide-induced γ-H2AX foci to a greater extent in MCF-7 than in HEK293 cells. The two cells also displayed differential patterns in the nuclear expression of DNA DSB repair proteins, which could, in part, explain the cytotoxic effects of sodium butyrate.ConclusionsThese studies suggest that sodium butyrate treatment leads to a different degree of chromatin relaxation in HEK293 and cancerous MCF-7 cells, which results in differential sensitivity to the toxic effects of etoposide in controlling damaged DNA repair.

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“…This effect sensitizes cells to DNA double-strand breaks, a genotoxic event playing a critical role in cancer cell survival [ 61 ]. Other anticancer drugs, such as bortezomib, imatinib, and histone deacetylase inhibitors, target homologous recombination [ 62 – 64 ]. This evidence might encourage further studies to test the effect of pomegranate extract in association with the anticancer drugs above reported.…”

Section: Anticancer Activity Of Pomegranate Polyphenolsmentioning

confidence: 99%

Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy

Turrini

Ferruzzi

Fimognari

2015

Oxidative Medicine and Cellular Longevity

146

107

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Cancer is the second leading cause of death and is becoming the leading one in old age. Vegetable and fruit consumption is inversely associated with cancer incidence and mortality. Currently, interest in a number of fruits high in polyphenols has been raised due to their reported chemopreventive and/or chemotherapeutic potential. Pomegranate has been shown to exert anticancer activity, which is generally attributed to its high content of polyphenols. This review provides a comprehensive analysis of known targets and mechanisms along with a critical evaluation of pomegranate polyphenols as future anticancer agents. Pomegranate evokes antiproliferative, anti-invasive, and antimetastatic effects, induces apoptosis through the modulation of Bcl-2 proteins, upregulates p21 and p27, and downregulates cyclin-cdk network. Furthermore, pomegranate blocks the activation of inflammatory pathways including, but not limited to, the NF-κB pathway. The strongest evidence for its anticancer activity comes from studies on prostate cancer. Accordingly, some exploratory clinical studies investigating pomegranate found a trend of efficacy in increasing prostate-specific antigen doubling time in patients with prostate cancer. However, the genotoxicity reported for pomegranate raised certain concerns over its safety and an accurate assessment of the risk/benefit should be performed before suggesting the use of pomegranate or its polyphenols for cancer-related therapeutic purposes.

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Inhibition of homologous recombination with vorinostat synergistically enhances ganciclovir cytotoxicity

Cited by 15 publications

References 48 publications

Exogenous p53 and ASPP2 expression enhances rAdV-TK/GCV-induced death in hepatocellular carcinoma cells lacking functional p53

Exogenous p53 and ASPP2 expression enhances rAdV-TK/GCV-induced death in hepatocellular carcinoma cells lacking functional p53

Histone deacetylase inhibitor sodium butyrate suppresses DNA double strand break repair induced by etoposide more effectively in MCF-7 cells than in HEK293 cells

Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy

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