Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells

Ovejero-Sánchez, María; Asensio-Juárez, Gloria; González, Myriam; Puebla, Pilar; Vicente‐Manzanares, Miguel; Peláez, Rafael; González-Sarmiento, Rogelio; Herrero, Ana B.

doi:10.3390/ijms232113019

Cited by 6 publications

(2 citation statements)

References 64 publications

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“…For example, histone deacetylase class IIa inhibitor with lenvatinib synergistically inhibited the growth of hepatocellular carcinoma cells [22]. Panobinostat synergistically enhanced the cytotoxicity of microtubule destabilizing drugs in ovarian cancer cells [23]. In addition, hybrids of HDACis and camptothecin also exhibited potent antitumor activity in A549 and HCT-116 cells [24].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of Biotin-SN38-Valproic Acid Conjugates

Zhang

et al. 2023

Molecules

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Despite the strong anticancer activity of SN38 (7-ethyl-10-hydroxy-camptothecin), the severe side effects and loss of anticancer activity caused by the lack of selectivity to cancer cells and hydrolysis of ring E prevent its clinical application. To address the issue, herein a multifunctional SN38 derivative (compound 9) containing biotin (tumor-targeting group) and valproic acid (histone deacetylase inhibitor, HDACi) was synthesized via click chemistry and evaluated using MTT assay. The in vitro cytotoxicity study showed that compound 9 exhibited superior cytotoxicity than irinotecan against human cervical cancer HeLa cells, albeit it was inferior to SN38. More significantly, compound 9 significantly reduced toxicity in mouse embryonic fibroblast NIH3T3 cells, indicating that compound 9 had the capacity to enhance tumor targeting due to its cell selectivity. Further studies demonstrated that, compared with irinotecan, compound 9 induced similar apoptosis of cancer cells. Consequently, compound 9 can not only improve its tumor-targeting ability mediated by biotin but also exert potent anticancer activity through the effect of SN38 and valproic acid, indicating that the design concept is an effective strategy for the structural modification of SN38.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Antitumor Evaluation of Biotin-SN38-Valproic Acid Conjugates

Zhang

et al. 2023

Molecules

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“…HDAC classes I, II and IV NSCLC 90 Multiple myeloma 91 Ovarian cancer 92,93 Glioblastoma NSCLC 110 Acute myeloid leukemia 111 Merkel cell carcinoma 112 Breast cancer 113 In this context, treating tumor cells with these inhibitors can disrupt different biological processes including gene transcription, replication and DDR. Most of them show enzymatic inhibition occupying the site of the substrate in their binding pockets 114 .…”

Section: Panobinostatmentioning

confidence: 99%

The role of VRK1 in chromatin remodeling: regulation of histone post-translational modifications and epigenetic enzymes

Monte Serrano

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DNA organization is essential for proper chromatin packaging and necessary to facilitate different processes that require dynamic chromatin remodeling. Modulation of chromatin structure is critical for the regulation of gene expression, since it determines which genes are accessible for transcription and the sequential recruitment of regulatory factors to the underlying DNA. Thus, to deal with inaccessible chromatin, eukaryotic cells have developed mechanisms that facilitate the opening of chromatin. Epigenetic alterations are defined as mechanisms that control DNA accessibility for the regulation of gene expression patterns and normal development. The epigenetic transcriptional control can occur through DNA methylation, histone post-translational modifications (PTMs), the reading of these modifications by epigenetic enzymes, histone-variants exchange, and noncoding RNA. Errors in the epigenetic regulation can alter the control of chromatin-based processes, ultimately leading to abnormal gene expression. Pathological conditions such as cancers, metabolic disorders, and inflammatory and neurodegenerative diseases have been found to be related to epigenetic errors. Post-translational modifications (PTMs) of the N-terminal tail of histones regulate DNA access. Importantly, histone PTMs are reversible, and their coordination requires a tight regulation of multiple epigenetic enzymes, known as writers (enzymes that add a mark) and erasers (enzymes that remove a mark) 111 . Among the different PTMs, acetylation and methylation are especially important. They have been extensively investigated in a context of cancer and therapy responses. The balance between de-and acetylation is controlled by deacetylases (HDACs) and acetyltransferases (HATs), while de-and methylation are regulated by demethylases (KDMs) and methyltransferases (KMTs).

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