Vorinostat is genotoxic and epigenotoxic in the mouse bone marrow cells at the human equivalent doses

Attia, Sabry M.; Al-Khalifa, Mohamed K.; Al-Hamamah, Mohammed A.; Alotaibi, Moureq R.; Attia, Mohamed S.M.; Ahmad, Sheikh F.; Ansari, Mushtaq Ahmad; Nadeem, Ahmed; Bakheet, Saleh A.

doi:10.1016/j.tox.2020.152507

Cited by 11 publications

(6 citation statements)

References 57 publications

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“…In another study, JQ1 inhibitor was reported to increase the apoptotic cell rate from 6-48% in leukemia and lymphoma cell lines (Mertz et al, 2011). Vorinostat increased apoptosis in mouse bone marrow (Attia et al, 2020), also while causing an apoptotic rate of 5% in HL60 cells, it was increased to 20% in combination with decitabine (Young et al, 2017). So, we detected higher apoptosis rates reaching ~ 98% rather than in the literature.…”

Section: Discussioncontrasting

confidence: 46%

HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents’ combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model

Alçıtepe

Salcin²,

Karatekin³

et al. 2022

Med Oncol

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The process of cancer initiation and development is regulated via the transcriptional expression of cells going under genomic and epigenetic changes. Targeting epigenetic "readers", i.e. bromodomains (BRD) and post-translational modi cations of nucleosomal histone proteins regulate gene expression in both cancerous and healthy cells.In this study, the new epigenetic agent BRD inhibitor PLX51107 and histone deacetylase (HDAC) inhibitor SAHA' s (vorinostat) single/combined applications' re ections were analyzed in case of cell proliferation, cytotoxicity, apoptosis, cell cycle arrest, and nally target gene expression regulation upon both AML and healthy B-lymphocyte cells; HL60 and NCI-BL2171, respectively; in vitro.Since mono treatments of either Vorinostat or Plx51107 regulated cellular responses such as growth, proliferation, apoptosis, and cell cycle arrest of tumor cells; their combination treatments exerted accelerated results. We detected that combined treatment of Plx51107 and vorinostat strengthened effects detected upon leukemic cells for gaining more sensitization to the agents, decreasing cell proliferation, dramatically inducing apoptosis, and cell cycle arrest; thus regulating target gene expressions. We have shown for the rst time that the newly analyzed BRD inhibitor Plx51107 could be a promising therapeutic approach for hematological malignancies and its mono or combined usage might support a rapid transition to clinical trials.

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Section: Discussioncontrasting

confidence: 46%

HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents’ combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model

Alçıtepe

Salcin²,

Karatekin³

et al. 2022

Med Oncol

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“…A better understanding of the still not fully resolved mechanisms behind the occurrence of DNA damage after HDAC inhibitor treatment is a central issue with regard to the therapeutic use of these substances and the development of novel inhibitors. In fact, HDAC inhibitors have been described as genotoxic or mutagenic agents in a number of reports in malignant [ 122 , 123 , 124 ] as well as in nonmalignant cells [ 125 , 126 , 127 , 128 ]. From these findings, the question arises as to whether HDAC inhibitors have a carcinogenic potential, which would be especially relevant when considering their therapeutic use in younger patients and/or in nononcological diseases.…”

Section: Molecular Mechanisms Of Hdaci-promoted Anticancer Effectsmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

124

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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“…Therefore, the observation that this histone sumoylation switch is powerfully controlled by ∆9THC is of great relevance to the issue of chromosomal mis-segregation during anaphase and cytokinesis subsequent to cannabis exposure [117]. Ubiquitin-like-specific protease 2 (ulp2) is inhibited by ∆9THC, which blocks desumoylation and thereby disrupts the integrity of the sumoylation code [116].…”

Section: Epigenomic Control Of Chromosomal Centromeric Functionmentioning

confidence: 99%

“…Administration of ∆9THC to dividing cells thus causes major disruptions of the kinetochore signaling to the SAC and leads to errors of chromosomal segregation [116]. ∆9THC also directly affects murine double minute 2 (mdm2) and SUMO-1 protein major binding partners of P53, which is well-known as the classical "guardian of the genome" [117]. Through interference with mdm2 and SUMO-1, ∆9THC activates P53 directly.…”

Section: Epigenomic Control Of Chromosomal Centromeric Functionmentioning

confidence: 99%

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

Reece

Hulse

2022

IJERPH

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The use of Δ8THC is increasing at present across the USA in association with widespread cannabis legalization and the common notion that it is “legal weed”. As genotoxic actions have been described for many cannabinoids, we studied the cancer epidemiology of Δ8THC. Data on 34 cancer types was from the Centers for Disease Control Atlanta Georgia, substance abuse data from the Substance Abuse and Mental Health Services Administration, ethnicity and income data from the U.S. Census Bureau, and cannabinoid concentration data from the Drug Enforcement Agency, were combined and processed in R. Eight cancers (corpus uteri, liver, gastric cardia, breast and post-menopausal breast, anorectum, pancreas, and thyroid) were related to Δ8THC exposure on bivariate testing, and 18 (additionally, stomach, Hodgkins, and Non-Hodgkins lymphomas, ovary, cervix uteri, gall bladder, oropharynx, bladder, lung, esophagus, colorectal cancer, and all cancers (excluding non-melanoma skin cancer)) demonstrated positive average marginal effects on fully adjusted inverse probability weighted interactive panel regression. Many minimum E-Values (mEVs) were infinite. p-values rose from 8.04 × 10−78. Marginal effect calculations revealed that 18 Δ8THC-related cancers are predicted to lead to a further 8.58 cases/100,000 compared to 7.93 for alcoholism and −8.48 for tobacco. Results indicate that between 8 and 20/34 cancer types were associated with Δ8THC exposure, with very high effect sizes (mEVs) and marginal effects after adjustment exceeding tobacco and alcohol, fulfilling the epidemiological criteria of causality and suggesting a cannabinoid class effect. The inclusion of pediatric leukemias and testicular cancer herein demonstrates heritable malignant teratogenesis.

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Vorinostat is genotoxic and epigenotoxic in the mouse bone marrow cells at the human equivalent doses

Cited by 11 publications

References 57 publications

HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents’ combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model

HDAC inhibitor Vorinostat and BET inhibitor Plx51107 epigenetic agents’ combined treatments exert a therapeutic approach upon acute myeloid leukemia cell model

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

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