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Antitumor activity of histone deacetylase inhibitor chidamide alone or in combination with epidermal growth factor receptor tyrosine kinase inhibitor icotinib in NSCLC.

ABSTRACT: The study was performed to investigate the antitumor efficacy of histone deacetylase inhibitor (HDACi) chidamide alone or with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) icotinib in non-small cell lung cancer (NSCLC). The cell viability, cell cycle, apoptosis, protein expression, and the molecular mechanisms were explored among ten NSCLC cell lines with chidamide and icotinib alone or in combination, and further validated in xenograft models of nude mice. Chidamide significantly reduced the viability of A549, HCC827, HCC827IR (icotinib resistant) cells, increased the sensitivity of icotinib synergistically in EGFR-TKI resistant cell line, especially in H1975 cells. Chidamide alone or combined with icotinib induced cell cycle arrest by inhibiting the activation of RAS/MAPK, PI3K/AKT and/or JAK/STAT pathways, and caused apoptosis by activating caspase 3 and PARP. Chidamide alone or with icotinib suppressed ?-catenin expression in HCC827, HCC827IR, and H1975 cells. The sensitivity of H1975 cells to icotinib was increased by chidamide through restoring E-cadherin expression. Furthermore, chidamide alone or in combination with icotinib inhibited HCC827IR and H1975 xenograft growth in athymic nude mice, respectively, with no appreciable side effects. Chidamide or combinating with icotinib exhibits antitumor activity in NSCLC cells, and has potential clinical implication for the treatment of NSCLC.

SUBMITTER: Zhang N

PROVIDER: S-EPMC6400687 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Antitumor activity of histone deacetylase inhibitor chidamide alone or in combination with epidermal growth factor receptor tyrosine kinase inhibitor icotinib in NSCLC.

Zhang Ningning N Liang Caixia C Song Wenya W Tao Dan D Yao Jiarui J Wang Shuai S Ma Li L Shi Yuankai Y Han Xiaohong X

Journal of Cancer 20190129 5

The study was performed to investigate the antitumor efficacy of histone deacetylase inhibitor (HDACi) chidamide alone or with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) icotinib in non-small cell lung cancer (NSCLC). The cell viability, cell cycle, apoptosis, protein expression, and the molecular mechanisms were explored among ten NSCLC cell lines with chidamide and icotinib alone or in combination, and further validated in xenograft models of nude mice. Chidamide sig ...[more]

PMID: 30854137

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Project description:BackgroundPeripheral T-cell lymphomas (PTCLs) are a heterogeneous group of neoplasms characterized by a poor prognosis. Histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for PTCLs. In this study, we aimed to explore the immunomodulatory effect of the HDAC inhibitor chidamide on circulating PD-1(+) cells from patients with PTCL, as well as its correlation with treatment response.MethodsWe enrolled newly diagnosed patients with PTCLs treated with a combination of chidamide and chemotherapy. Gene expression profile analysis was performed on peripheral blood PD-1(+) cells, both at baseline and at the end of treatment. A list of differentially expressed genes (DEGs) was identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to annotate the biological implications of the DEGs. A gene concept network was constructed to identify the key DEGs for further PCR verification.ResultsA total of 302 DEGs were identified in the complete remission (CR) group, including 162 upregulated and 140 downregulated genes. In contrast, only 12 DEGs were identified in the non-CR group. GO analysis revealed that these upregulated DEGs were mainly involved in chemokine activity, cell chemotaxis, and cellular response to interleukin-1 and interferon-γ. Furthermore, KEGG pathway analysis showed that these DEGs were enriched in cytokine-cytokine receptor interaction and chemokine signaling pathways. The innate immune signaling pathways, including the Toll-like and NOD-like receptor signaling pathways, were also influenced. The gene concept network revealed that the key upregulated genes belonged to the C-C chemokine family.ConclusionOur results showed that chidamide treatment notably enhanced the expression of genes associated with chemokine activity and chemotaxis function of circulating PD-1(+) cells. By recruiting immune cells and improving the innate immune function of PD-1(+) cells, chidamide may reshape the tumor microenvironment to an anti-tumor phenotype and synergize with checkpoint inhibitors.

Dataset Information

Antitumor activity of histone deacetylase inhibitor chidamide alone or in combination with epidermal growth factor receptor tyrosine kinase inhibitor icotinib in NSCLC.

Publications

Antitumor activity of histone deacetylase inhibitor chidamide alone or in combination with epidermal growth factor receptor tyrosine kinase inhibitor icotinib in NSCLC.

Similar Datasets

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