CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance <i>via</i> HDAC2 inhibition in chronic myeloid leukemia

Zhang, Tianzhuo; Wei, Danna; Lü, Tingting; Ma, Dan; Yu, Kunlin; Fang, Qin; Zhang, Zhaoyuan; Wang, Weili; Wang, Jishi

doi:10.1039/c9ra07971h

Cited by 5 publications

(5 citation statements)

References 42 publications

(55 reference statements)

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“…SCA, a powerful and specific HDAC2 inhibitor, has been demonstrated to effectively suppresses tumour progression both in vitro and in vivo. 48 , 49 In our study, aberrant HDAC2 overexpression led to the transcriptional silencing of NLRP3 and suppressed cancer cell pyroptosis. Targeting HDAC2 with the small‐molecule inhibitor SCA increased the efficacy of anticancer drugs in xenografts and PDX models.…”

Section: Discussionsupporting

confidence: 54%

“…Our findings support the utility of HDAC2 inhibitors in colorectal treatment. SCA, a powerful and specific HDAC2 inhibitor, has been demonstrated to effectively suppresses tumour progression both in vitro and in vivo 48,49 . In our study, aberrant HDAC2 overexpression led to the transcriptional silencing of NLRP3 and suppressed cancer cell pyroptosis.…”

Section: Discussionmentioning

confidence: 49%

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Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD‐mediated pyroptosis in colorectal cancer

Guan,

Liu,

Wang

et al. 2024

Clinical & Translational Med

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BackgroundAlthough numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear.MethodsPyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase‐Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient‐derived xenograft models were constructed to validate the effects of the drug combinations.ResultsAs the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)‐mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac‐mediated recruitment of the BRD4‐p‐P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5‐fluorouracil or regorafenib) in CRC xenograft‐bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p‐P65/NLRP3 and is a prognostic factor for CRC patients.ConclusionCollectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD‐mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy.Highlights Silencing of NLRP3 limits the GSDMD‐dependent pyroptosis in colorectal cancer. HDAC2‐mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p‐P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 49%

Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD‐mediated pyroptosis in colorectal cancer

Guan,

Liu,

Wang

et al. 2024

Clinical & Translational Med

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“…CAY10683, an inhibitor of HDACs, in combination with imatinib. exerted synergistic effects on imatinib resistance by inhibiting HDAC2 and the PI3K/Akt signal transduction pathway in chronic myelogenous leukemia (CML) cells with imatinib resistance [107] .…”

Section: The Role Of Hdac2 In Anti-cancer Drug Resistancementioning

confidence: 99%

HDAC2 as a target for developing anti-cancer drugs

Jo¹,

Shim²,

Kim³

et al. 2023

Computational and Structural Biotechnology Journal

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“…Interestingly, a combined therapy of santacruzamate A with tacedinaline showed growth inhibition, cell cycle progression changes, and apoptosis induction in the HepG2 and Huh7 cell lines. Additionally, Zhang, et al [ 145 ] showed that the combined treatment of santacruzamate A with imatinib exerted a synergistic effect on the inhibition of cell viability, induction of apoptosis, and cell cycle arrest in the G2/M phase in imatinib-resistant chronic myeloid leukemia (CML) cells. At the same time, it produced minimal effects on normal CD34 + cells.…”

Section: Marine Cyanobacterial Metabolites With Cytotoxic Antiprolife...mentioning

confidence: 99%

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects

et al. 2022

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The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules’ origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.

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CAY10683 and imatinib have synergistic effects in overcoming imatinib resistance via HDAC2 inhibition in chronic myeloid leukemia

Abstract: Imatinib (IM) is utilized for targeting the BCR–ABL fusion protein and as such, chronic myeloid leukemia (CML) is considered to be a curable disorder for which patients can achieve a long survival.

Cited by 5 publications

References 42 publications

Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD‐mediated pyroptosis in colorectal cancer

Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD‐mediated pyroptosis in colorectal cancer

HDAC2 as a target for developing anti-cancer drugs

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects

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