Novel alkoxyamide-based histone deacetylase inhibitors reverse cisplatin resistance in chemoresistant cancer cells

Asfaha, Yodita; Schrenk, Christian; Avelar, Leandro A. Alves; Lange, Friedrich; Wang, Chenyin; Bandolik, Jan J.; Hamacher, Alexandra; Kassack, Matthias U.; Kurz, Thomas

doi:10.1016/j.bmc.2019.115108

Cited by 22 publications

(24 citation statements)

References 15 publications

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“…Chemical structures of the HDACi tested are summarized in Supplementary Figure S1. HDAC inhibitory activity of the compounds was confirmed by analyses of hyperacetylation of histones as concluded from enzyme assays and cellular HDAC pan assays [20,30,33,79,82].…”

Section: Methodsmentioning

confidence: 86%

“…Of note, HDACi can impair genetic stability by epigenetic mechanisms and by affecting the acetylation of proteins that are involved in the regulation of DNA repair and the DNA damage response (DDR), such as X-ray repair cross-complementing protein 6 (Ku-70), Ataxia telangiectasia mutated kinase (ATM), checkpoint kinases (Chk1,2), the nuclear protein kinase WEE1, the tumor suppressor p53, the DNA mismatch repair protein MSH2, and breast cancer-associated proteins (BRCA) [ 1 , 24 , 25 , 26 , 27 , 28 ]. By interfering with mechanisms of DDR and DNA repair, including the repair of broken replication forks [ 29 ], HDACi increase the anticancer efficacy of various conventional (i.e., genotoxic) anticancer drugs and radiation [ 25 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. Hence, HDACi are suggested as particular powerful anticancer drugs, especially if used in combination treatment regimen [ 22 , 36 , 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 86%

Section: Introductionmentioning

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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“…Cisplatin and paclitaxel can be usually used in ovarian cancer chemotherapy. Asfaha et al reported that the novel HDAC inhibitors can increase the sensitivity of cisplatin in cisplatin-resistant cancer cells (86). Another study showed that P. gingivalis can induce paclitaxel resistance through activating the Notch1 pathway in oral squamous cell carcinoma (87).…”

Section: The Microbiome In Cancer Treatmentmentioning

confidence: 99%

Opportunities and Challenges of the Human Microbiome in Ovarian Cancer

et al. 2020

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Ovarian cancer is the most lethal malignancy among gynecological cancers worldwide. Most ovarian cancer patients are diagnosed at an advanced stage because of non-specific clinical symptoms. The human microbiome plays a crucial role in maintaining the normal physiological and pathological state of the body. With the development of technologies such as DNA and 16S rRNA sequencing, an increasing number of findings on the role of microbiome in cancers are being reported. Microbiome abnormalities are increasingly associated with diseases, including cancer development, and response to therapies. Some studies have shown the relationship between microbiome changes and ovarian cancer. However, the mechanisms underlying this relationship are not yet fully understood. Here, we summarize the key findings in this regard by focusing on estrogen metabolism and host recognition receptors in microorganisms and changes in the gut or pelvic microbiome in patients with ovarian cancer. We further discuss the potential of using the microbiome as a novel biomarker for cancers. We also highlight the possibility to use microorganisms as a treatment modality to enhance the immune system, activate anti-tumor response, mediate chemotherapy resistance, and ameliorate the adverse effects of the treatment.

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“…Histone acetylation induced by HDACi can prevent NFκB-induced cisplatin resistance and thus enhancing the cytotoxicity following cisplatin treatment. In addition, a newly synthesized HDACi, 13d, can enhance the cytotoxicity of cisplatin to cisplatin-resistant TSCC cell line (Cal27CisR) through caspase-3/7 pathways ( 18 ) in vitro . Another study demonstrated that radiotherapy combined with HDACi was also feasible in the treatment of HNSCC ( 19 ) (SQD9, SCC61, Cal27, SC179).…”

Section: Acetylationmentioning

confidence: 99%

Protein Post-translational Modifications in Head and Neck Cancer

Wang

2020

Front. Oncol.

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Head and neck cancer (HNC) is one of the most common malignant tumors worldwide, and is prone to tumor recurrence and metastasis. At present, surgery combined with radiotherapy and chemotherapy is still the conventional treatment modality for patients with HNC. However, for patients with relapse or metastasis of HNC, the treatment outcome is not ideal, and the prognosis is poor. Thus, it is crucial to deepen the understand of tumor mechanisms. Post-translational modifications (PTMs) refer to covalent binding of small chemical molecular groups to amino-acid side-chain of proteins. Post-translational modification is an important regulator of protein function, and as such, a current research hotspot of epigenetics. In recent years, it has been found that tumor occurrence is often accompanied by the abnormality of PTMs. Indeed, the abnormality play an important role in tumor development, and can be used as a target for tumor diagnosis and treatment. To date, several types of protein PTMs involved in the development of HNC have been reported. This paper reviews the relationship between HNC and several major protein PTMs, including acetylation, methylation, and glycosylation, in order to provide clues for the future application about PTMs in diagnosis and treatment of HNC.

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Novel alkoxyamide-based histone deacetylase inhibitors reverse cisplatin resistance in chemoresistant cancer cells

Cited by 22 publications

References 15 publications

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

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

Opportunities and Challenges of the Human Microbiome in Ovarian Cancer

Protein Post-translational Modifications in Head and Neck Cancer

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