A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results

Coronel, Jaime; Cetina, Lucely; Pacheco, Irlanda; Trejo-Becerril, Catalina; González-Fierro, Aurora; Cruz-Hernández, Erick de la; Pérez-Cárdenas, Enrique; Taja‐Chayeb, Lucía; Arias-Bofill, Daymi; Candelaria, Myrna; Vidal, Sílvia; Dueñas‐González, Alfonso

doi:10.1007/s12032-010-9700-3

Cited by 114 publications

(72 citation statements)

References 41 publications

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“…So far, the combination of hydralazine and valproate has shown efficacy against myelodysplastic syndrome and a number of solid tumors (39,(43)(44)(45)(46) however, whether their clinical usefulness rely on their effect upon key processes of cancer such as proliferation, and apoptosis or on their effect upon the immune response to tumor remains to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Chávez‐Blanco

Cruz-Hernández²,

Domínguez³

et al. 2011

Int J Oncol

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Abstract. Natural killer cells play a role in the immune antitumor response by recognizing and eliminating tumor cells through the engagement of NKG2D receptors with their ligands on target cells. This work aimed to investigate whether epigenetic drugs are able to increase MICA and MICB expression as well as NK cell cytotoxicity. Prostate, colon, breast and cervical cancer cell lines were analyzed for the expression of MICA and MICB at the mRNA and protein levels by RT-PCR, Western blot, flow cytometry and ELISA. The activating mark H3K4m2 at the MICA and MICB promoters was investigated by ChIP assays. Cytotoxicity of NK cells against the target epithelial cancer cells was investigated with the CD107 cytotoxicity assay. The results show that hydralazine and valproic acid not only increase the expression of MICA and MICB ligands of target cells, but also reduce their shedding to the supernatant. This upregulation occurs at the transcriptional level as revealed by increase of the H3K4 activating mark at the promoter of MICA and MICB genes. These effects are paralleled by increased cytotoxicity of NK cells, which was attenuated at different degrees by using blocking antibodies against the NKG2D receptor and ligands. In conclusion, our results demonstrate the ability of hydralazine and valproate to increase the NK activity against epithelial cancer cell lines and suggest that these drugs could reduce the levels of soluble MICA and MICB helping in avoiding tumor-induced suppression of NK cytotoxicity against the tumor.

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Section: Discussionmentioning

confidence: 99%

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Chávez‐Blanco

Cruz-Hernández²,

Domínguez³

et al. 2011

Int J Oncol

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“…Patients treated with these compounds enjoyed significantly greater progression-free survival compared to those that received cisplatin topotecan and placebo alone. 110 …”

Section: Nonnucleoside Analogsmentioning

confidence: 99%

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

Johnson

Akman²,

Calimport³

et al. 2012

Rejuvenation Research

328

218

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DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

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“…The progression-free survival in the epigenetics + cisplatin group was 10 months, compared with 6 months in the cisplatin + placebo group (p < 0.05), and there was a trend towards greater rates of overall survival, objective response, and stable disease in the epigenetics group [Coronel et al 2011]. In another gynecological malignancy, a phase II trial in 17 heavily pretreated and platinum-resistant ovarian cancer patients demonstrated resensitization to carboplatin after treatment with DAC [Matei et al 2012].…”

Section: Chemosensitizationmentioning

confidence: 99%

Epigenetic therapy in gastrointestinal cancer: the right combination

Abdelfatah

Kerner

Nanda

et al. 2016

Therap Adv Gastroenterol

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Abstract:Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.

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A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results

Cited by 114 publications

References 41 publications

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

Upregulation of NKG2D ligands and enhanced natural killer cell cytotoxicity by hydralazine and valproate

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

Epigenetic therapy in gastrointestinal cancer: the right combination

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