SAHA, an HDAC inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin

Park, Seong Joon; Kim, Seung‐Mi; Moon, Jai‐Hee; Kim, Jeong Hee; Shin, Jae‐Sik; Sheng, Hong; Shin, Yong-June; Lee, Dae-Hee; Lee, Eun Young; Hwang, In-Sun; Kim, Jeong Eun; Kim, Kyu-Pyo; Hong, Yong Sang; Lee, Won-Keun; Choi, Eun Kyung; Lee, Jung Shin; Jin, Dayong; Kim, Tae Won

doi:10.1007/s13277-015-4216-2

Cited by 18 publications

(14 citation statements)

References 20 publications

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“…In HCC827IR cells, chidamide down-regulated the expression and activation of EGFR and MET, and mainly inhibited the RAS/MAPK pathway. A recent study showed that HDAC inhibitor SAHA activated the phosphorylation of EGFR and increased the cell sensitivity to erlotinib in pancreatic cancer 32. However, in the present study, chidamide monotherapy did not have obvious effect on signal pathway in H1975 cells, but when combined with a relatively high concentration of icotinib, the PI3K/AKT pathway was significantly inhibited, which resulted in arresting cell cycle and promoting apoptosis.…”

Section: Discussioncontrasting

confidence: 80%

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

Liang¹,

Song²,

Tao³

et al. 2019

J. Cancer

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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 β-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.

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Section: Discussioncontrasting

confidence: 80%

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

Liang¹,

Song²,

Tao³

et al. 2019

J. Cancer

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“…Some of these agents, including the pan‐HDAC inhibitors vorinostat (suberoylanilide hydroxamic acid [SAHA]) and panobinostat (LBH589), are now US Food and Drug Administration‐approved anticancer drugs . Several previous studies demonstrated that the combination of an EGFR‐TKI (eg, gefitinib or erlotinib) with an HDAC inhibitor (eg, MS‐275, SAHA, LBH589, MPT0E028, or YF454A) enhanced their effects, including the induction of apoptosis and the inhibition of growth in glioblastoma, pancreatic cancer, head and neck cancer, and lung cancer cells . However, whether the combination of osimertinib with an HDAC inhibitor exerts enhanced effects against EGFR‐mutant NSCLC cell lines that have acquired resistance to osimertinib has not been well studied and thus is the focus of the current study.…”

Section: Introductionmentioning

confidence: 99%

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

Zang

Qian

Zong

et al. 2020

Cancer

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BACKGROUND:The major clinical obstacle that limits the long-term benefits of treatment with osimertinib (AZD9291) in patients with epidermal growth factor receptor-mutant non-small cell lung cancer is the development of acquired resistance. Therefore, effective strategies that can overcome acquired resistance to osimertinib are urgently needed. The authors' current efforts in this direction have identified LBH589 (panobinostat), a clinically used histone deacetylase inhibitor, as a potential agent in overcoming osimertinib resistance. METHODS: Cell growth and apoptosis in vitro were evaluated by measuring cell numbers and colony formation and by detecting annexin V-positive cells and protein cleavage, respectively. Drug effects on tumor growth in vivo were assessed with xenografts in nude mice. Alterations of tested proteins in cells were monitored with Western blot analysis. Gene knockout was achieved using the CRISPR/ Cas9 technique. RESULTS: The combination of LBH589 and osimertinib synergistically decreased the survival of different osimertinibresistant cell lines, including those harboring C797S mutations, with greater inhibition of cell colony formation and growth. The combination enhanced the induction of apoptosis in osimertinib-resistant cells. Importantly, the combination effectively inhibited the growth of osimertinib-resistant xenograft tumors in nude mice. Mechanistically, the combination of LBH589 and osimertinib enhanced the elevation of Bim in osimertinib-resistant cells. Knockout of Bim in osimertinib-resistant cells substantially attenuated or abolished apoptosis enhanced by the LBH589 and osimertinib combination. These results collectively support a critical role of Bim elevation in the induction of apoptosis of osimertinib-resistant cells for this combination. CONCLUSIONS: The current findings provide strong preclinical evidence in support of the potential for LBH589 to overcome osimertinib resistance in the clinic.

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“…However, in pancreatic cancer, erlotinib is not widely used. Numerous studies have been performed in an effort to overcome erlotinib resistance in pancreatic cancer, investigating the use of inhibitors of MEK [9, 10], AKT2 [11,12], HDACs [13], and PI3K/mTOR [10,12].…”

Section: Discussionmentioning

confidence: 99%

Silencing of the DJ-1 (PARK7) gene sensitizes pancreatic cancer to erlotinib inhibition

Sun

Fan

et al. 2019

Preprint

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Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, in combination with gemcitabine, has been shown to be a promising therapy in the treatment of pancreatic cancer. Our previous study showed that DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. The aim of this study was to evaluate whether silencing DJ-1 expression can sensitize pancreatic cancer cells to erlotinib treatment. METHODS: Knockdown of DJ-1 expression, combined with erlotinib treatment, was performed in the pancreatic cancer cell lines BxPC-3, PANC-1 and MiaPACa-2. Cell proliferation was assessed with the CCK-8 assay and BrdU incorporation, while apoptosis was measured using terminal deoxynucleotidyl ransferase (TdT)-mediated dUTP nick-end labeling. RAS activity and activation of the downstream pathways involving AKT and ERK1/2 were explored to determine the underlying mechanism. RESULTS: Knockdown of DJ-1 expression accelerated erlotinib-induced cell apoptosis, and improved the inhibitory effect of erlotinib on pancreatic cancer cell proliferation in vitro and in xenograft tumor growth in vivo . Knockdown of DJ-1 decreased K-RAS expression, membrane translocation, and activity in BxPC-3 cells. Knockdown of DJ-1 also decreased K-RAS, H-RAS, and N-RAS expression in PANC-1 and MiaPACa-2 cells. Knockdown of DJ-1 synergistically inhibited AKT and ERK1/2 phosphorylation with erlotinib in pancreatic cancer cells. CONCLUSIONS: DJ-1 may activate the RAS pathway, reinforcing erlotinib drug resistance. Blocking DJ-1 in combination with the EGFR tyrosine kinase inhibitor erlotinib may be an attractive therapeutic target in pancreatic cancer.

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SAHA, an HDAC inhibitor, overcomes erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin

Cited by 18 publications

References 20 publications

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

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

Overcoming acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589)

Silencing of the DJ-1 (PARK7) gene sensitizes pancreatic cancer to erlotinib inhibition

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