Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

Farooq, Muhammad; El‐Faham, Ayman; Khattab, Sherine N.; Elkayal, Ahmed M.; Ibrahim, Mahmoud F.; Taha, Nael Abu; Baabbad, Almohannad; Wadaan, Muhammad A.; Hamed, Ezaat A.

doi:10.7314/apjcp.2014.15.18.7785

Cited by 11 publications

(7 citation statements)

References 54 publications

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“…Therefore, anti-angiogenic therapies have been the spearhead of cancer therapeutics for decades ( Ferrara and Kerbel, 2005 ; Jain, 2008 ; Heath and Bicknell, 2009 ), yet cancer largely remains incurable despite these advances in anti-angiogenesis research. VPA is also presented to be anti-angiogenic to alter angiogenicity in human cancers ( Chelluri et al, 2016 ; Zhao et al, 2016 ), and is also currently undergoing clinical evaluation for anti-cancer therapy ( Bezecny, 2014 ; Farooq et al, 2014 ; Yadav et al, 2015 ; Kwiecinska et al, 2016 ; Proske et al, 2016 ; Igarashi et al, 2017 ; Nilubol et al, 2017 ; Ramadoss et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Valproic Acid Induces Endothelial-to-Mesenchymal Transition-Like Phenotypic Switching

et al. 2018

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Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is a widely used anticonvulsant drug that is currently undergoing clinical evaluation for anticancer therapy due to its anti-angiogenic potential. Endothelial cells (ECs) can transition into mesenchymal cells and this form of EC plasticity is called endothelial-to-mesenchymal transition (EndMT), which is widely implicated in several pathologies including cancer and organ fibrosis. However, the effect of VPA on EC plasticity and EndMT remains completely unknown. We report herein that VPA-treatment significantly inhibits tube formation, migration, nitric oxide production, proliferation and migration in ECs. A microscopic evaluation revealed, and qPCR, immunofluorescence and immunoblotting data confirmed EndMT-like phenotypic switching as well as an increased expression of pro-fibrotic genes in VPA-treated ECs. Furthermore, our data confirmed important and regulatory role played by TGFβ-signaling in VPA-induced EndMT. Our qPCR array data performed for 84 endothelial genes further supported our findings and demonstrated 28 significantly and differentially regulated genes mainly implicated in angiogenesis, endothelial function, EndMT and fibrosis. We, for the first time report that VPA-treatment associated EndMT contributes to the VPA-associated loss of endothelial function. Our data also suggest that VPA based therapeutics may exacerbate endothelial dysfunction and EndMT-related phenotype in patients undergoing anticonvulsant or anticancer therapy, warranting further investigation.

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Section: Introductionmentioning

confidence: 99%

Valproic Acid Induces Endothelial-to-Mesenchymal Transition-Like Phenotypic Switching

et al. 2018

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“…The results show that all VA compounds presented more activity than VPA (see Table 5), hence indicating that the molecular design of these derivatives was clever in generating new molecules that fullled the desired goal. 31 In this case the molecular design gained credibility, due to the fact that this simple derivative augmented the biological response due to the recovery of the hydrogen-bonding group nearby, where it was originally placed in VPA. Furthermore, this modication not only recovers this interaction due to the presence of the aromatic ring, the biological effect is also enhanced by at least 4 times in U373 cells and almost 16 times in C6 cells.…”

Section: Cell Viability Of Va 1-7mentioning

confidence: 99%

Novel valproic aminophenol amides with enhanced glial cell viability effect

Alpuche-García¹,

Dávila-González²,

Arregui³

et al. 2017

RSC Adv.

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“…Valproic acid (VPA) has been used for the treatment of some types of cancer, including haematologic malignancies. [ 2 ] However, some studies have demonstrated that VPA is hepatotoxic due to its reactive metabolites 4‐ene‐valproic acid (4‐ene‐VPA) and 2,4‐diene‐valproic acid (2,4‐diene‐VPA), which are enzymatically generated by cytochrome P‐450 (CYP). Moreover, VPA metabolism induces hepatocyte membrane lysis and ROS formation.…”

Section: Introductionmentioning

confidence: 99%

Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies

Mendieta-Wejebe

Silva-Trujillo

Bello

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives N‐(2‐hydroxyphenyl)‐2‐propylpentanamide (HO‐AAVPA), a derivative of valproic acid (VPA), has been proposed as a potential anticancer agent due to its improved antiproliferative effects in some cancer cell lines. Although there is evidence that VPA is metabolized by cytochrome P450 2C11 rat isoform, HO‐AAVPA CYP‐mediated metabolism has not yet been fully explored. Therefore, in this work, the biotransformation of HO‐AAVPA by CYP2C11 was investigated. Methods Kinetic parameters and spectral interaction between HO‐AAVPA and CYP were evaluated using rat liver microsomes. The participation of CYP2C11 in metabolism of HO‐AAVPA was confirmed by cimetidine (CIM) inhibition assay. Docking and molecular dynamics simulations coupled to MMGBSA methods were used in theoretical study. Key findings HO‐AAVPA is metabolized by CYP enzymes (KM = 38.94 µm), yielding a hydroxylated metabolite according to its HPLC retention time (5.4 min) and MS analysis (252.2 m/z). In addition, CIM inhibition in rat liver microsomes (Ki = 59.23 µm) confirmed that CYP2C11 is mainly involved in HO‐AAVPA metabolism. Furthermore, HO‐AAVPA interacts with CYP2C11 as a type I ligand. HO‐AAVPA is stabilized at the CYP2C11 ligand recognition site through a map of interactions similar to other typical CYP2C11 substrates. Conclusion Therefore, rat liver CYP2C11 isoform is able to metabolize HO‐AAVPA.

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Biological Screening of Novel Derivatives of Valproic Acid for Anticancer and Antiangiogenic Properties

Cited by 11 publications

References 54 publications

Valproic Acid Induces Endothelial-to-Mesenchymal Transition-Like Phenotypic Switching

Valproic Acid Induces Endothelial-to-Mesenchymal Transition-Like Phenotypic Switching

Novel valproic aminophenol amides with enhanced glial cell viability effect

Exploring the biotransformation of N-(2-hydroxyphenyl)-2-propylpentanamide (an aryl valproic acid derivative) by CYP2C11, using in silico predictions and in vitro studies

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