Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

Ranganna, Kasturi; Selvam, Chelliah; Shivachar, Amruthesh C.; Yousefipour, Zivar

doi:10.3390/ijms21218198

Cited by 21 publications

(13 citation statements)

References 157 publications

(334 reference statements)

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“…For example, proliferation of chronic lymphatic leukemia cells was inhibited via downregulation of antiapoptotic Bcl-2 family members [ 211 ]. CUDC-907 evades drug resistance and also showed effects in myc-driven lymphoma cells [ 212 ]. Next to the increase in apoptosis in prostate cancer cells, CUDC-907 also mediated antiproliferative effects through inducing DNA damage [ 213 ].…”

Section: Combination Strategiesmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

124

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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Section: Combination Strategiesmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

124

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“…In the present study, we use a dual PI3K and HDAC inhibitor, CUDC-907 or Fimepinostat, and show its potency in inhibiting NB growth. CUDC-907 is a first-in-class, oral small molecule dual HDAC (class I and II) and PI3K (class Iα, β, and δ) inhibitor that can simultaneously target multiple oncogenic signaling pathways [ 17 , 18 ]. CUDC-907 is effective in multiple cancer types, including acute myeloid leukemia, relapsed or refractory diffuse large B-cell lymphoma, prostate cancer, thyroid cancer, and multiple myeloma [ 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

Chilamakuri

Agarwal

2022

Cancers

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The dysregulation of PI3K, HDACs, and MYCN are well known for promoting multiple cancer types, including neuroblastoma (NB). Targeting the upstream regulators of MYCN, including HDACs and PI3K, was shown to suppress cancer growth. In the present study, we analyze different NB patient datasets to reveal that high PI3K and HDAC expression is correlated with overall poor NB patient survival. High PI3K level is also found to be associated with high MYCN level and NB stage progression. We repurpose a dual inhibitor CUDC-907 as a single agent to directly target both PI3K and HDAC in NB. We use in vitro methodologies to determine the efficacy and selectivity of CUDC-907 using six NB and three control fibroblast cell lines. Our results show that CUDC-907 significantly inhibits NB proliferation and colony growth, induces apoptosis, blocks cell cycle progression, inhibits MYCN, and enhances H3K9Ac levels by inhibiting the PI3K/AKT signaling pathway and HDAC function. Furthermore, CUDC-907 significantly inhibits NB tumor growth in a 3D spheroid tumor model that recapitulates the in vivo tumor growth. Overall, our findings highlight that the dual inhibition of PI3K and HDAC by CUDC-907 is an effective therapeutic strategy for NB and other MYC-dependent cancers.

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“…They possess various effects such as anti‐inflammatory and antioxidant. At present, they are studied as many non‐neoplastic diseases including non‐alcoholic fatty liver disease, pulmonary fibrosis and heart failure 30 . And in present study, histone deacetylase inhibitor ACY1215 was selected to be intervention agent to observe itself potential protective effect in ALF.…”

Section: Discussionmentioning

confidence: 99%

HDAC6 inhibitor ACY1215 inhibits the activation of NLRP3 inflammasome in acute liver failure by regulating the ATM/F‐actin signalling pathway

Chen

Wang

Jiao

et al. 2021

J Cellular Molecular Medi

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Acute liver failure (ALF) is a rare and critical medical condition. This study was designed to investigate the protective effects and underlying mechanism of ACY1215 in ALF mice. Our findings suggested that ACY1215 treatment ameliorates the pathological hepatic damage of ALF and decreases the serum levels of ALT and AST. Furthermore, ACY1215 pretreatment increased the level of ATM, γ‐H2AX, Chk2, p53, p21, F‐actin and vinculin in ALF. Moreover, ACY1215 inhibited the level of NLRP3, ASC, caspase‐1, IL‐1β and IL‐18 in ALF. The ATM inhibitor KU55933 could decrease the level of ATM, γ‐H2AX, Chk2, p53, p21, F‐actin and vinculin in ALF with ACY1215 pretreatment. The F‐actin inhibitor cytochalasin B decreased the level of F‐actin and vinculin in ALF with ACY1215 pretreatment. However, cytochalasin B had no effect on protein levels of ATM, Chk2, p53 and p21 in ALF with ACY1215 pretreatment. Cytochalasin B could dramatically increase the level of NLRP3, ASC, caspase‐1, IL‐1β and IL‐18 in ALF with ACY1215 pretreatment. These results indicated that ACY1215 exhibited hepatoprotective properties, which was associated with the inhibition of NLRP3 inflammasome, and this effect of ACY1215 was connected with upregulation of the ATM/F‐actin mediated signalling pathways.

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Histone Deacetylase Inhibitors as Multitarget-Directed Epi-Drugs in Blocking PI3K Oncogenic Signaling: A Polypharmacology Approach

Cited by 21 publications

References 157 publications

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

HDAC6 inhibitor ACY1215 inhibits the activation of NLRP3 inflammasome in acute liver failure by regulating the ATM/F‐actin signalling pathway

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