The Histone Deacetylase Inhibitor Valproic Acid Sensitizes Gemcitabine-Induced Cytotoxicity in Gemcitabine-Resistant Pancreatic Cancer Cells Possibly Through Inhibition of the DNA Repair Protein Gamma-H2AX

Wang, Yufeng; Kuramitsu, Yasuhiro; Kitagawa, Takao; Tokuda, Kazuhiro; Baron, Bruno; Akada, Junko; Nakamura, Kazuyuki

doi:10.1007/s11523-015-0370-0

Cited by 13 publications

(12 citation statements)

References 32 publications

(38 reference statements)

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“…There is also evidence that elevating histone H3 acetylation may sensitize cancer cells to chemotherapeutics [25,26]. VPA promotes cisplatin sensitivity [27] and restores erlotinib [28], sorafenib [29], gemcitabine, and vincristine responsiveness [30,31]. Recent investigations demonstrate that VPA may also act on temsirolimus-resistant bladder cancer [13] and everolimus-resistant renal cell carcinoma cells [14].…”

Section: Discussionmentioning

confidence: 99%

Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

Makarević

Rutz

Juengel

et al. 2019

Cancers

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The mechanistic target of rapamycin (mTOR) is elevated in prostate cancer, making this protein attractive for tumor treatment. Unfortunately, resistance towards mTOR inhibitors develops and the tumor becomes reactivated. We determined whether epigenetic modulation by the histone deacetylase (HDAC) inhibitor, valproic acid (VPA), may counteract non-responsiveness to the mTOR inhibitor, temsirolimus, in prostate cancer (PCa) cells. Prostate cancer cells, sensitive (parental) and resistant to temsirolimus, were exposed to VPA, and tumor cell growth behavior compared. Temsirolimus resistance enhanced the number of tumor cells in the G2/M-phase, correlating with elevated cell proliferation and clonal growth. The cell cycling proteins cdk1 and cyclin B, along with Akt-mTOR signaling increased, whereas p19, p21 and p27 decreased, compared to the parental cells. VPA significantly reduced cell growth and up-regulated the acetylated histones H3 and H4. Cdk1 and cyclin B decreased, as did phosphorylated mTOR and the mTOR sub-complex Raptor. The mTOR sub-member Rictor and phosphorylated Akt increased under VPA. Knockdown of cdk1, cyclin B, or Raptor led to significant cell growth reduction. HDAC inhibition through VPA counteracts temsirolimus resistance, probably by down-regulating cdk1, cyclin B and Raptor. Enhanced Rictor and Akt, however, may represent an undesired feedback loop, which should be considered when designing future therapeutic regimens.

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Section: Discussionmentioning

confidence: 99%

Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

Makarević

Rutz

Juengel

et al. 2019

Cancers

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“…Valproic acid was shown to enhance the cytotoxic effect on gynecologic cancer cells in combination with an aurora kinase inhibitor [40]. Valproic acid was also reported to sensitize gemcitabine-induced cytotoxicity in gemcitabine-resistant pancreatic cancer cells [41].…”

Section: Resultsmentioning

confidence: 99%

Synthetic lethality guiding selection of drug combinations in ovarian cancer

et al. 2019

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BackgroundSynthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.Materials and methodsWe established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.ResultsTwelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies.ConclusionA set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

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“…An evaluation of the histone acetylation status revealed increased aH3 and aH4 expression in the resistant and sensitive cells, suggesting an epigenetic mechanism [ 63 ]. Recent investigations have shown that VPA also promotes cisplatin sensitivity [ 64 ] and restores erlotinib [ 65 ], sorafenib [ 66 ], gemcitabine, and vincristine responsiveness [ 67 , 68 ]. However, the specific molecular mechanisms need to be verified in future research.…”

Section: Application Of the Epigenetic Effect Of Antiepileptic Drugsmentioning

confidence: 99%

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

Kong

Zhong

2020

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An epigenetic effect mainly refers to a heritable modulation in gene expression in the short term but does not involve alterations in the DNA itself. Epigenetic molecular mechanisms include DNA methylation, histone modification, and untranslated RNA regulation. Antiepileptic drugs have drawn attention to biological and translational medicine because their impact on epigenetic mechanisms will lead to the identification of novel biomarkers and possible therapeutic strategies for the prevention and treatment of various diseases ranging from neuropsychological disorders to cancers and other chronic conditions. However, these transcriptional and posttranscriptional alterations can also result in adverse reactions and toxicity in vitro and in vivo. Hence, in this review, we focus on recent findings showing epigenetic processes mediated by antiepileptic drugs to elucidate their application in medical experiments and shed light on epigenetic research for medicinal purposes.

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The Histone Deacetylase Inhibitor Valproic Acid Sensitizes Gemcitabine-Induced Cytotoxicity in Gemcitabine-Resistant Pancreatic Cancer Cells Possibly Through Inhibition of the DNA Repair Protein Gamma-H2AX

Abstract: These results indicate that VPA enhances GEM-induced cytotoxicity in GEM-resistant pancreatic cancer cells, possibly through inhibition of DNA damage signaling and repair. Our study suggests VPA as a potential therapeutic agent for combinatorial treatment with GEM in pancreatic cancer.

Cited by 13 publications

References 32 publications

Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

Influence of the HDAC Inhibitor Valproic Acid on the Growth and Proliferation of Temsirolimus-Resistant Prostate Cancer Cells In Vitro

Synthetic lethality guiding selection of drug combinations in ovarian cancer

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

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