Novel α,β-unsaturated hydroxamic acid derivatives overcome cisplatin resistance

Pflieger, Marc; Hamacher, Alexandra; Öz, Taner; Horstick‐Muche, Nadine; Boesen, Benedikt; Schrenk, Christian; Kassack, Matthias U.; Kurz, Thomas

doi:10.1016/j.bmc.2019.07.052

Cited by 7 publications

(6 citation statements)

References 23 publications

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“…For the platinum complexes cisplatin and carboplatin, an inverse correlation with the expression of HDAC2 protein was found, while the potency of oxaliplatin inversely correlates with the expression of the Sirt6 protein and with HDAC4 and Sirt5 in a positive manner. Several studies have shown that various HDAC inhibitors such as SAHA and other hydroxamic acid derivatives increase cisplatin toxicity in cancer cells or can circumvent cisplatin resistance [ 39 , 40 , 41 , 42 , 43 ], supporting the association between the activity of cisplatin or carboplatin and the expression of HDAC2. Interestingly, for another clinically used platinum complex, oxaliplatin, a reverse correlation with the Sirt6 expression (not significant), as well as a significant positive correlation with HDAC4 and Sirt5 expression were found.…”

Section: Discussionmentioning

confidence: 99%

Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors

Behnisch-Cornwell

Grathwol

Schulig

et al. 2021

Cancers

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Inhibiting the activity of histone deacetylase (HDAC) is an ongoing strategy in anticancer therapy. However, to our knowledge, the relationships between the expression of HDAC proteins and the antitumor drug sensitivity of cancer cells have not been studied until now. In the current work, we investigated the relative expression profiles of 10 HDAC isoenzymes comprising the classes I–III (HDAC1/2/4/6; Sirt1/2/3/5/6/7) in a panel of 17 cancer cell lines, including the breast, cervix, oesophageal, lung, oral squamous, pancreas, as well as urinary bladder carcinoma cells. Correlations between the data of mRNA expression for these enzymes obtained from the National Cancer Institute (NCI) 60 cancer cell line program were also examined. Next, we performed univariate analysis between the expression patterns of HDAC/Sirt isoenzymes with the sensitivity of a 16 cell panel of cancer cell lines towards several antitumor drugs. In a univariate correlation analysis, we found a strong relation between Sirt2 expression and cytotoxicity caused by busulfan, etoposide, and hydroxyurea. Moreover, it was identified that Sirt5 correlates with the effects exerted by oxaliplatin or topotecan, as well as between HDAC4 expression and these two drugs. Correlations between the data of mRNA expression for enzymes with the potencies of the same anticancer agents obtained from the NCI 60 cancer cell line program were also found, but none were the same as those we found with our protein expression data. Additionally, we report here the effects upon combination of the approved HDAC inhibitor vorinostat and one other known inhibitor trichostatin A as well as newer hetero-stilbene and diazeno based sirtuin inhibitors on the potency of cisplatin, lomustine, and topotecan. For these three anticancer drugs, we found a significantly enhanced cytotoxicity when co-incubated with HDAC inhibitors, demonstrating a potentially beneficial influence of HDAC inhibition on anticancer drug treatment.

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Section: Discussionmentioning

confidence: 99%

Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors

Behnisch-Cornwell

Grathwol

Schulig

et al. 2021

Cancers

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“…Synthesis and biological activities of the HDAC inhibitory compounds KSK64 [30] and DDK137 [79] were already described. More detailed information regarding the synthesis of the various HDACi is also provided by Pflieger et al [80], Mackwitz et al [81], and Krieger et al [82]. Chemical structures of the HDACi tested are summarized in Supplementary Figure S1.…”

Section: Methodsmentioning

confidence: 99%

“…Chemical synthesis of HDACi has already been described in detail [30,[79][80][81][82]. Chemicals and solvents were purchased from commercial suppliers (Sigma-Aldrich, (Taufkirchen, Germany); Acros Organics (Schwerte, Germany); TCI chemicals (Eschborn, Germany); Fluorochem ABCR (Karlsruhe, Germany); Alfa Aesar (Kandel, Germany); J&K chemicals (Altdorf, Germany); Carbolution (Saarbrücken, Germany)) and used without further purification.…”

Section: Chemical Synthesis Of Hdaci-reaction Monitoring Purificatimentioning

confidence: 99%

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

Friedrich

Assmann

Schumacher

et al. 2020

IJMS

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Histone deacetylase inhibitors (HDACi) are already approved for the therapy of leukemias. Since they are also emerging candidate compounds for the treatment of non-malignant diseases, HDACi with a wide therapeutic window and low hazard potential are desirable. Here, we investigated a panel of 12 novel hydroxamic acid- and benzamide-type HDACi employing non-malignant V79 hamster cells as toxicology guideline-conform in vitro model. HDACi causing a ≥10-fold preferential cytotoxicity in malignant neuroblastoma over non-malignant V79 cells were selected for further genotoxic hazard analysis, including vorinostat and entinostat for control. All HDACi selected, (i.e., KSK64, TOK77, DDK137 and MPK77) were clastogenic and evoked DNA strand breaks in non-malignant V79 cells as demonstrated by micronucleus and comet assays, histone H2AX foci formation analyses (γH2AX), DNA damage response (DDR) assays as well as employing DNA double-strand break (DSB) repair-defective VC8 hamster cells. Genetic instability induced by hydroxamic acid-type HDACi seems to be independent of bulky DNA adduct formation as concluded from the analysis of nucleotide excision repair (NER) deficient mutants. Summarizing, KSK64 revealed the highest genotoxic hazard and DDR stimulating potential, while TOK77 and MPK77 showed the lowest DNA damaging capacity. Therefore, these compounds are suggested as the most promising novel candidate HDACi for subsequent pre-clinical in vivo studies.

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“…Two types of BRDi were synthesized, +JQ1-based (ASK series) and I-BET 762based (PWK series) inhibitors. The synthesis of the HDAC class I/IIb (KSK64, LAK31, LAK39, LAK41 and YAK61) [29][30][31], pan (MPK409) [32], class I (K79PCHy) [33] and class IIb (MPK187 and MPK377) [34] inhibitors have been previously described. To evaluate the importance of class I selective inhibitors, two types of class I selective inhibitors were designed and synthesized, RGFP109-based (LAK78, LAK86, LAK88, LAK92, LAK94, LAK96, LAK98 and LAK100) and Entinostat-based inhibitors (LAK102 and LAK104).…”

Section: Synthesis Of Novel Inhibitorsmentioning

confidence: 99%

Establishment and Evaluation of Dual HDAC/BET Inhibitors as Therapeutic Options for Germ Cell Tumors and Other Urological Malignancies

Burmeister

Stephan

Avelar

et al. 2022

Molecular Cancer Therapeutics

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Urologic malignancies represent major challenges for clinicians with annually rising incidences. Additionally, cisplatin treatment-induced long-term toxicities and the development of therapy resistance emphasize the need for novel therapeutics. In this study, we analyzed the effects of novel histone deacetylase (HDAC) and bromodomain and extraterminal domain-containing (BET) inhibitors to combine them into a potent HDAC-BET-fusion molecule and understanding their molecular mode-of-action. Treatment of (cisplatin-resistant) germ cell tumors (GCT), urothelial, renal and prostate carcinoma cells with the HDAC, BET, and dual inhibitors decreased cell viability, induced apoptosis and affected the cell cycle. Furthermore, a dual inhibitor considerably decreased tumor burden in GCT xenograft models. On a molecular level, correlating RNA- to ATAC-sequencing data indicated a considerable induction of gene expression, accompanied by site-specific changes of chromatin accessibility after HDACi application. Upregulated genes could be linked to intra- and extra-cellular trafficking, cellular organization and neuronal processes including neuroendocrine differentiation. Regarding chromatin accessibility on a global level, an equal distribution of active or repressed DNA accessibility has been detected after HDAC inhibitor treatment, questioning the current understanding of HDAC inhibitor function. In summary, our HDAC, BET, and dual inhibitors represent a new treatment alternative for urological malignancies. Furthermore, we shed light on new molecular and epigenetic mechanisms of the tested epi-drugs, allowing for a better understanding of the underlying modes-of-action and risk assessment for the patient.

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Novel α,β-unsaturated hydroxamic acid derivatives overcome cisplatin resistance

Cited by 7 publications

References 23 publications

Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors

Correlation Analysis of Protein Expression of 10 HDAC/Sirtuin Isoenzymes with Sensitivities of 23 Anticancer Drugs in 17 Cancer Cell Lines and Potentiation of Drug Activity by Co-Treatment with HDAC Inhibitors

In Vitro Assessment of the Genotoxic Hazard of Novel Hydroxamic Acid- and Benzamide-Type Histone Deacetylase Inhibitors (HDACi)

Establishment and Evaluation of Dual HDAC/BET Inhibitors as Therapeutic Options for Germ Cell Tumors and Other Urological Malignancies

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