Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors

Zang, Yan; Kirk, Christopher J.; Johnson, Daniel E.

doi:10.4161/cbt.29452

Cited by 22 publications

(10 citation statements)

References 48 publications

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“…Although a range of single agent CFZ IC 50 values were observed across the five molecularly diverse cell lines tested, a consistent trend for synergy with SAHA was observed for all cell lines at both 48 and 72 hours of treatment. Our results in NSCLC are similar to observations of synergy that have been made in non-Hodgkin lymphoma models where the HDAC6 inhibitor ricolinostat was synergistic with CFZ (Dasmahapatra et al 2014), in mantle cell lymphoma (MCL) where SAHA and SNDX-275 were shown to be synergistic with CFZ (Dasmahapatra et al 2011), and in head and neck carcinoma models where HDAC inhibitors were shown to be synergistic with CFZ (Zang et al 2014). Comparable to the observations made in MCL, we observed an increase in ROS when SAHA was combined with CFZ.…”

Section: Discussionsupporting

confidence: 88%

Carfilzomib combined with suberanilohydroxamic acid (SAHA) synergistically promotes endoplasmic reticulum stress in non-small cell lung cancer cell lines

Hanke

Garland

Baker

2015

J Cancer Res Clin Oncol

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Purpose The endoplasmic reticulum (ER) stress response is a therapeutic target for pharmacologic intervention in cancer cells. We hypothesized that combining carfilzomib (CFZ), a proteasome inhibitor, and vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor, would synergistically activate ER stress in non-small cell lung cancer (NSCLC) cell lines resulting in enhanced anti-tumor activity. Methods Five NSCLC cell lines were treated with CFZ, SAHA, or the combination and cell proliferation measured using the MTT assay. Calcusyn software was utilized to determine the combination index as a measure of synergy. Cell viability and cytotoxicity were measured using trypan blue exclusion, CellTiter and CytoTox assays. Western blot was used to measure markers of apoptosis, ER stress, and oxidative stress related proteins. Reactive oxygen species (ROS) was measured using the fluorophore CM-H2DCFDA. Results Synergistic activity was observed for all cell lines following 48 and 72 hours of combined treatment. H520 and A549 cell lines were used to assess viability and apoptosis. In both cell lines, increased death and cleaved caspase-3 was observed following combination treatment as compared with single agent treatments. Combination therapy was associated with upregulation of ER stress regulated proteins including activating transcription factor 4, GRP78/BiP, and C/EBP homologous protein. Both cell lines also showed increased ROS and the oxidative stress-related protein, heat shock protein 70. Conclusion Combining proteasome inhibition with HDAC inhibition enhances ER stress which may contribute to the synergistic anti-cancer activity observed in NSCLC cell lines. Further pre-clinical and clinical studies of CFZ + SAHA in NSCLC are warranted.

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Section: Discussionsupporting

confidence: 88%

Carfilzomib combined with suberanilohydroxamic acid (SAHA) synergistically promotes endoplasmic reticulum stress in non-small cell lung cancer cell lines

Hanke

Garland

Baker

2015

J Cancer Res Clin Oncol

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“…Cells were lysed and subjected to immunoblotting as previously described (43). Blots were probed with antibodies against NRF2, Mcl-1, Bik (Santa Cruz Biotechnology), phospho-STAT3, total STAT3, Bcl-X L , Bax, Bak (Cell Signaling), Bcl-2 (Dako), Bim (Stressgen Bioreagents), and β-actin (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane

Bauman

Zang

Sen

et al. 2016

Cancer Prevention Research

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Chronic exposure to carcinogens represents the major risk factor for head and neck squamous cell carcinoma (HNSCC). Beverages derived from broccoli sprout extracts (BSEs) that are rich in glucoraphanin and its bioactive metabolite sulforaphane promote detoxication of airborne pollutants in humans. Herein, we investigated the potential chemopreventive activity of sulforaphane using in vitro models of normal and malignant mucosal epithelial cells and an in vivo model of murine oral cancer resulting from the carcinogen 4-nitroquinoline-1-oxide (4NQO). Sulforaphane treatment of Het-1A, a normal mucosal epithelial cell line, and 4 HNSCC cell lines led to dose- and time-dependent induction of NRF2 and the NRF2 target genes NQO1 and GCLC, known mediators of carcinogen detoxication. Sulforaphane also promoted NRF2-independent dephosphorylation/inactivation of pSTAT3, a key oncogenic factor in HNSCC. Compared to vehicle, sulforaphane significantly reduced the incidence and size of 4NQO-induced tongue tumors in mice. A pilot clinical trial in 10 healthy volunteers evaluated the bioavailability and pharmacodynamic activity of three different BSE regimens, based upon urinary sulforaphane metabolites and NQO1 transcripts in buccal scrapings, respectively. Ingestion of sulforaphane-rich BSE demonstrated the greatest, most consistent bioavailability. Mucosal bioactivity, defined as 2-fold or greater upregulation of NQO1 mRNA, was observed in 6 of 9 evaluable participants ingesting glucoraphanin-rich BSE; 3 of 6 ingesting sulforaphane-rich BSE; and 3 of 9 after topical-only exposure to sulforaphane-rich BSE. Together, our findings demonstrate preclinical chemopreventive activity of sulforaphane against carcinogen-induced oral cancer, and support further mechanistic and clinical investigation of sulforaphane as a chemopreventive agent against tobacco-related HNSCC.

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“…Low or moderate levels of autophagy appear cell-protective, while high levels of autophagy facilitate promotion of cell death [ 102 , 103 ]. Notwithstanding these facts, multiple studies showed that inhibition of autophagy increased PI-induced apoptosis [ 39 , 101 , 122 , 134 , 153 ]. Upon PI treatment, protective autophagy was activated in several solid malignancies [ 101 , 122 ].…”

Section: Resistance and Predictive Factors In Solid Malignanciesmentioning

confidence: 99%

“…Another combination therapy that reduced PI-induced protective autophagy was noted for a histone deacetylase 6 (HDAC6) inhibitor. This combination increased BTZ-induced apoptosis and reversed PI-resistance [ 39 , 122 , 153 ].…”

Section: Resistance and Predictive Factors In Solid Malignanciesmentioning

confidence: 99%

Positioning of proteasome inhibitors in therapy of solid malignancies

Roeten

Cloos

Jansen

2017

Cancer Chemother Pharmacol

123

109

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Targeting of the protein degradation pathway, in particular, the ubiquitin-proteasome system, has emerged as an attractive novel cancer chemotherapeutic modality. Although proteasome inhibitors have been most successfully applied in the treatment of hematological malignancies, they also received continuing interest for the treatment of solid tumors. In this review, we summarize the current positioning of proteasome inhibitors in the treatment of common solid malignancies (e.g., lung, colon, pancreas, breast, and head and neck cancer), addressing topics of their mechanism(s) of action, predictive factors and molecular mechanisms of resistance.

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Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors

Cited by 22 publications

References 48 publications

Carfilzomib combined with suberanilohydroxamic acid (SAHA) synergistically promotes endoplasmic reticulum stress in non-small cell lung cancer cell lines

Carfilzomib combined with suberanilohydroxamic acid (SAHA) synergistically promotes endoplasmic reticulum stress in non-small cell lung cancer cell lines

Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane

Positioning of proteasome inhibitors in therapy of solid malignancies

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