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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

Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors

Experimetnal Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy
Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori di Napoli IRCCS “Fondazione Pascale”, 80131 Naples, Italy
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
These authors share senior authorship.
Academic Editor: David Wong
Cancers 2022, 14(3), 695;
Received: 23 December 2021 / Revised: 24 January 2022 / Accepted: 27 January 2022 / Published: 29 January 2022
Fluoropyrimidines represent the backbone of many combination chemotherapy regimens for the treatment of solid cancers but are still associated with toxicity and mechanisms of resistance. In this review, we focused on the epigenetic modifiers histone deacetylase inhibitors (HDACis) and on their ability to regulate specific genes and proteins involved in the fluoropyrimidine metabolism and resistance mechanisms. We presented emerging preclinical and clinical studies, highlighting the mechanisms by which HDACis can prevent/overcome the resistance and/or enhance the therapeutic efficacy of fluoropyrimidines, potentially reducing their toxicity, and ultimately improving the overall survival of cancer patients.
Although fluoropyrimidines were introduced as anticancer agents over 60 years ago, they are still the backbone of many combination chemotherapy regimens for the treatment of solid cancers. Like other chemotherapeutic agents, the therapeutic efficacy of fluoropyrimidines can be affected by drug resistance and severe toxicities; thus, novel therapeutic approaches are required to potentiate their efficacy and overcome drug resistance. In the last 20 years, the deregulation of epigenetic mechanisms has been shown to contribute to cancer hallmarks. Histone modifications play an important role in directing the transcriptional machinery and therefore represent interesting druggable targets. In this review, we focused on histone deacetylase inhibitors (HDACis) that can increase antitumor efficacy and overcome resistance to fluoropyrimidines by targeting specific genes or proteins. Our preclinical data showed a strong synergistic interaction between HDACi and fluoropyrimidines in different cancer models, but the clinical studies did not seem to confirm these observations. Most likely, the introduction of increasingly complex preclinical models, both in vitro and in vivo, cannot recapitulate human complexity; however, our analysis of clinical studies revealed that most of them were designed without a mechanistic approach and, importantly, without careful patient selection. View Full-Text
Keywords: HDAC inhibitors; fluoropyrimidines; drug resistance HDAC inhibitors; fluoropyrimidines; drug resistance
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MDPI and ACS Style

Grumetti, L.; Lombardi, R.; Iannelli, F.; Pucci, B.; Avallone, A.; Di Gennaro, E.; Budillon, A. Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors. Cancers 2022, 14, 695.

AMA Style

Grumetti L, Lombardi R, Iannelli F, Pucci B, Avallone A, Di Gennaro E, Budillon A. Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors. Cancers. 2022; 14(3):695.

Chicago/Turabian Style

Grumetti, Laura, Rita Lombardi, Federica Iannelli, Biagio Pucci, Antonio Avallone, Elena Di Gennaro, and Alfredo Budillon. 2022. "Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors" Cancers 14, no. 3: 695.

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