Vorinostat synergizes with EGFR inhibitors in NSCLC cells by increasing ROS via up-regulation of the major mitochondrial porin VDAC1 and modulation of the c-Myc-NRF2-KEAP1 pathway

Leone, Alessandra; Roca, Maria Serena; Terranova-Barberio, Manuela; Vitagliano, Carlo; Ciliberto, Gennaro; Mancini, Rita; Gennaro, Elena Di; Bruzzese, Francesca; Budillon, Alfredo

doi:10.1016/j.freeradbiomed.2015.07.155

Cited by 74 publications

(51 citation statements)

References 64 publications

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“…Our group and many others have demonstrated the synergistic antitumor activity of HDACi in combination with a large number of structurally different anticancer agents, among which cisplatin and anti-EGFR agents [4–7]. Our group has recently demonstrated that the HDACi vorinostat, in combination with the EGFR-tyrosine kinase inhibitor gefitinib, induced synergistic inhibition of proliferation, migration and invasion as well as induction of apoptosis, in preclinical models of SCCHN and NSCLC, including cancer cell lines resistant to gefitinib and characterized by mesenchymal markers and phenotype.…”

Section: Rationalementioning

confidence: 99%

“…Our group has recently demonstrated that the HDACi vorinostat, in combination with the EGFR-tyrosine kinase inhibitor gefitinib, induced synergistic inhibition of proliferation, migration and invasion as well as induction of apoptosis, in preclinical models of SCCHN and NSCLC, including cancer cell lines resistant to gefitinib and characterized by mesenchymal markers and phenotype. The mechanism of the synergistic interaction is related to the ability of vorinostat to modulate the expression and the activity of ErbB receptors (EGFR, ErbB2 and ErbB3), to reverse EMT, and/or to alter redox homeostasis in gefitinib-resistant cells [5, 7, 29]. …”

Section: Rationalementioning

confidence: 99%

“…A large number of HDACi are currently in clinical development as anticancer agents, and three (vorinostat, romidepsin and belinostat) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma [2, 3],1 while panobinostat is the first HDAC inhibitor approved to treat multiple myeloma in combination with the proteasome inhibitor bortezomib and dexamethasone, in patients who have received at least two prior standard therapies 2. Our group and many others have demonstrated the synergistic antitumor activity of HDACi in combination with several chemotherapeutics and molecular targeted agents, including cisplatin and anti-epidermal growth factor receptor (EGFR) agents [4–7]. In details, we have recently demonstrated that the HDACi vorinostat, in combination with the EGFR-tyrosine kinase inhibitor gefitinib, induced synergistic inhibition of proliferation, migration and invasion as well as induction of apoptosis, in preclinical models of SCCHN, including cancer cell lines resistant to gefitinib and characterized by mesenchymal markers and phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

et al. 2016

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BackgroundRecurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to down regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition (EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic disorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may be to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the possible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR.Method/DesignV-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell carcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration of cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from day −14 with a titration strategy in each patient (target serum level of 50–100 μg/ml). Primary end point is the objective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size, calculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit for rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18 responses. Secondary endpoints are time to progression, duration of response, overall survival, safety.Objectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. γH2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory activity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and proteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different time points during treatment.DiscussionOverall, this study could provide a less toxic and more effective first-line chemotherapy regimen in patients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and efficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder patients, and will add insights in the mechanism of the synergistic interaction between these agents.EudraCT Number2014-001523-69Trial registrationClinicalTrials.gov number, NCT02624128

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Section: Rationalementioning

confidence: 99%

Section: Rationalementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

et al. 2016

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“…24) Several studies have provided evidence that vorinostat and dasatinib exhibit antitumor activity by inducing ROS generation and apoptosis. [25][26][27] Our results demonstrated that the incubation of MCF-7 cells with vorinostat and dasatinib, alone and in combination, increased the ROS generation, decreased ΔΨ m , down-regulated the anti-apoptosis protein Bcl-2 expression, and induced the mitochondria-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 59%

Synergistic Inhibition of Breast Cancer Cell Growth by an Epigenome-Targeting Drug and a Tyrosine Kinase Inhibitor

Yuan

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Nrf2 is a key transcription factor in the regulation of antioxidant and Phase II detoxification gene expression, and is activated by oxidative stress and the presence of electrophiles. It has been observed that Nrf2 exerts protective effects in both normal and cancer cells during cell stress, thereby serving key roles in the development of cancer, including gastric, and skin cancer (41)(42)(43)(44)(45). It is considered that Nrf2 protects cells from oxidative stress through overproduction of antioxidants and detoxification proteins (46,47).…”

Section: Discussionmentioning

confidence: 99%

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

Cheng¹,

Liang²,

Qi³

2017

Experimental and Therapeutic Medicine

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Abstract. Glaucoma is a major cause of irreversible blindness. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of numerous antioxidants within cells and is therefore a focus of current ophthalmic research. To determine the roles of Nrf2 in mediating the glaucoma trabecular meshwork (GTM), the present study evaluated the levels of Nrf2 expression in GTM and human trabecular meshwork (HTM) cells by reverse-transcription-quantitative polymerase chain reaction and western blot analysis. It was principally observed that Nrf2 expression was downregulated in GTM cells. In addition, to determine the influence of Nrf2 on the apoptosis and proliferation of GTM and HTM cells, transfection assays and western blotting were performed to evaluate the expression of apoptosis-related proteins. The results of the current study indicated that Nrf2 may promote viability and reduce apoptosis in GTM and HTM cells. Collectively, these data suggest that Nrf2 may be a novel therapeutic target to treat glaucoma.

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Vorinostat synergizes with EGFR inhibitors in NSCLC cells by increasing ROS via up-regulation of the major mitochondrial porin VDAC1 and modulation of the c-Myc-NRF2-KEAP1 pathway

Cited by 74 publications

References 64 publications

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

Phase II clinical study of valproic acid plus cisplatin and cetuximab in recurrent and/or metastatic squamous cell carcinoma of Head and Neck-V-CHANCE trial

Synergistic Inhibition of Breast Cancer Cell Growth by an Epigenome-Targeting Drug and a Tyrosine Kinase Inhibitor

Role of nuclear factor (erythroid-derived 2)-like 2 in the age-resistant properties of the glaucoma trabecular meshwork

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