Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells

Ammerpohl, Ole; Trauzold, Anna; Schniewind, Bodo; Griep, U; Pilarsky, Christian; Grützmann, Robert; Hd, Saeger; Janßen, Ottmar; Sipos, Bence; Klöppel, Günter; Kalthoff, Holger

doi:10.1038/sj.bjc.6603511

Cited by 49 publications

(34 citation statements)

References 43 publications

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“…Interestingly, TSA also downregulated this ABCC1 gene expression in H69VP drug-resistant cells (data not shown). Thus, our results support the idea that HDAC inhibitors could modulate MDR through simultaneous inhibition of different ABC transporters as recently suggested for 4-phenylbutyrate (Ammerpohl et al, 2007).…”

Section: Discussionsupporting

confidence: 91%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

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Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drugsensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drugsensitive cells, but strongly decreased it in drug-resistant cells. These up-and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter À50GC, À110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment.

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Section: Discussionsupporting

confidence: 91%

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

et al. 2007

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“…In line with these data there have been reported observations showing that the histone deacetylases inhibitor 4-phenylbutyrate, an agent known to increase gap junction communication capacity, enhances gemcitabinemediated apoptosis in pancreatic tumor cells (36). In this sense, another pharmacologic agent that is known to enhance GJIC and has proved benefits to gemcitabine treatment is tamoxifen.…”

Section: Discussionsupporting

confidence: 62%

Connexin-26 Is a Key Factor Mediating Gemcitabine Bystander Effect

Garcia-Rodríguez

Pérez-Torras

Carrió

et al. 2011

Molecular Cancer Therapeutics

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Gemcitabine is a nucleoside analogue with anticancer activity. Inside the cell, it is sequentially phosphorylated to generate the active drug. Phosphorylated nucleoside analogues have been shown to traffic through gap junctions. We investigated the participation of gap junctional intercellular communication (GJIC) as a possible mechanism spreading gemcitabine cytotoxicity in pancreatic tumors. Immunohistochemical analysis of pancreatic cancer biopsies revealed increased connexin 26 (Cx26) content but loss of connexins 32 (Cx32) and 43 (Cx43) expression. Cx26 abundance in neoplastic areas was confirmed by Cx26 mRNA in situ hybridization. Heterogeneity on the expression levels and the localization of Cx26, Cx32, and Cx43 were identified in pancreatic cancer cells and found to be associated with the extent of GJIC, and correlated with gemcitabine bystander cytotoxic effect. The abundance of Cx26 at the contact points in tumoral regions prompted us to study the involvement of Cx26 in the GJIC of gemcitabine toxic metabolites and their influence on the antitumoral effects of gemcitabine. Knockdown of Cx26 led to decreased GJIC and reduced gemcitabine bystander killing whereas overexpression of Cx26 triggered increased GJIC and enhanced the gemcitabine cytotoxic bystander effect. Gemcitabine treatment of mice bearing tumors, with a high GJIC capacity, resulted in a significant delay in tumor progression. Interestingly, gemcitabine administration in mice bearing tumors that overexpress Cx26 triggered a dramatic tumor regression of 50% from the initial volume. This study shows that Cx26 participates in the gap junction-mediated bystander cytoxic effect of gemcitabine and provides evidence that upregulation of Cx26 improves gemcitabine anticancer efficacy. Mol Cancer Ther; 10(3); 505-17. Ó2011 AACR.

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“…Efficacy of 4-PBA in alleviation of ER stress has been demonstrated in a variety of tissues in earlier studies, including ours (13,17,29). On the other hand, 4-PBA is also known to suppress histone deacetylase (HDAC) activity (1,16). Recently, Zhao et al (36) found that HDAC activity in lung tissue was significantly increased in patients with end-stage idiopathic PAH and in a rat model of hypoxiainduced PAH.…”

Section: Discussionmentioning

confidence: 95%

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

Koyama

Furuhashi

Ishimura

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Koyama M, Furuhashi M, Ishimura S, Mita T, Fuseya T, Okazaki Y, Yoshida H, Tsuchihashi K, Miura T. Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 306: H1314 -H1323, 2014. First published March 7, 2014 doi:10.1152/ajpheart.00869.2013.-Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositolrequiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH 2-terminal kinase and eukaryotic translation initiation factor-2␣ in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH. endoplasmic reticulum stress; chemical chaperone; pulmonary arterial hypertension; vascular smooth muscle cell; platelet-derived growth factor; inflammation PULMONARY ARTERIAL HYPERTENSION (PAH) is characterized by vasoconstriction, micro-thrombosis, and vascular remodeling in the pulmonary vasculature and progresses insidiously with dismal outcomes (26). The pathogenesis of PAH is not fully understood, but growth factor receptors, protease-activated receptor-2, increased elastase activity, dysfunction of ion channels (voltage-dependent K ϩ and transient receptor potential channels), loss of adenomatous polyposis coli-␣3 integrin interaction, and inflammatory cytokines have been suggested to be involved in proliferation of vascular cells in the lung (2,5,15,24). Vasodilatory agents, including prostanoids, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE5) inhibitors, h...

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Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells

Cited by 49 publications

References 43 publications

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

Connexin-26 Is a Key Factor Mediating Gemcitabine Bystander Effect

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

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