The Proteasome Inhibitor MG-132 Protects Hypoxic SiHa Cervical Carcinoma Cells after Cyclic Hypoxia/Reoxygenation from Ionizing Radiation

Pajonk, Frank; Grumann, Thorsten; McBride, William H.

doi:10.1593/neo.06634

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…Further, recent reports demonstrate proteasome inhibitor-induced activation of EGFR as well as EGFR-independent mechanisms can induce MAPK, AKT and STAT3 prosurvival pathways, as observed here. 9,19, 32-34 Additionally, while proteasome inhibitors radiosensitized cancer cells and smaller xenograft tumors in experimental models, 15-17 they may enhance radioprotection of SCC tumor cells under hypoxic conditions, 35 such as occur in large SCCHN in advanced stage patients. Cytokines and angiogenesis factors expressed by SCCHN in response to prosurvival 26 and hypoxia signals 36 were detected in serum of all 7 patients pretreatment.…”

Section: Discussionmentioning

confidence: 99%

Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer

Argiris

Duffy

Kummar

et al. 2011

Clinical Cancer Research

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PURPOSE A phase I clinical trial and molecular correlative studies were performed to evaluate preclinical evidence for combinatorial activity of proteasome inhibitor bortezomib, epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. EXPERIMENTAL DESIGN Patients with radiotherapy-naïve stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0 and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity modulated radiotherapy (IMRT), delivered in 2Gy fractions to 70-74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens, and the cell line UMSCC-1. RESULTS Seven patients were accrued before the study was terminated when 5/6 previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (PFS =4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; 1 patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease. Expected grade 3 toxicities included radiation mucositis (n=4), dermatitis (n=1), and rash (n=1). SCCHN-related cytokines increased in serial serum specimens of patients developing progressive disease (P=0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. CONCLUSIONS Combining bortezomib with cetuximab and radiation therapy demonstrated unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling and SCCHN cytokine expression, warranting avoidance of this combination.

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Section: Discussionmentioning

confidence: 99%

Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer

Argiris

Duffy

Kummar

et al. 2011

Clinical Cancer Research

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“…The proteasome inhibitor MG132 increases p53 protein levels and transcriptional activity in human cervical cancer cell lines, providing for sensitization of the cells to TRAIL-receptor or Fas-mediated apoptosis [84] or radiosensitivity under hypoxic conditions [85]. Bortezomib (PS341, Velcade ® , Millennium Pharmaceuticals, Cambridge, MA, USA), with specificity for the chymotrypsin-like proteasome activity [86], has been shown to sensitize SiHa to radiotherapy via inhibition of the NF-ĸB pathway, in tumor xenografts induces caspase 3 cleavage and under hypoxic conditions decreases vascular endothelial growth factor (VEGF) production, affecting tumor growth [87,88].…”

Section: Development Of Novel Treatmentsmentioning

confidence: 99%

Therapy of Human Papillomavirus-Related Disease

Stern

Burg

Hampson

et al. 2012

Vaccine

157

124

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This chapter reviews the current treatment of chronic and neoplastic HPV-associated conditions and the development of novel therapeutic approaches. Surgical excision of HPV-associated lower genital tract neoplasia is very successful but largely depends on secondary prevention programmes for identification of disease. Only high-risk HPV-driven chronic, preneoplastic lesions and some very early cancers cannot be successfully treated by surgical procedures alone. Chemoradiation therapy of cervical cancer contributes to the 66–79% cervical cancer survival at 5 years. Outlook for those patients with persistent or recurrent cervical cancer following treatment is very poor. Topical agents such as imiquimod (immune response modifier), cidofovir (inhibition of viral replication; induction apoptosis) or photodynamic therapy (direct damage of tumour and augmentation of anti-tumour immunity) have all shown some useful efficacy (~50–60%) in treatment of high grade vulvar intraepithelial neoplasia. Provider administered treatments of genital warts include cryotherapy, trichloracetic acid, or surgical removal which has the highest primary clearance rate. Patient applied therapies include podophyllotoxin and imiquimod. Recurrence after “successful” treatment is 30–40%. Further improvements could derive from a rational combination of current therapy with new drugs targeting molecular pathways mediated by HPV in cancer. Small molecule inhibitors targeting the DNA binding activities of HPV E1/E2 or the anti-apoptotic consequences of E6/E7 oncogenes are in preclinical development. Proteasome and histone deacetylase inhibitors, which can enhance apoptosis in HPV positive tumour cells, are being tested in early clinical trials. Chronic high-risk HPV infection/neoplasia is characterised by systemic and/or local immune suppressive regulatory or escape factors. Recently two E6/E7 vaccines have shown some clinical efficacy in high grade VIN patients and this correlated with strong and broad systemic HPV-specific T cell response and modulation of key local immune factors. Treatments that can shift the balance of immune effectors locally in combination with vaccination are now being tested. This article forms part of a special supplement entitled “Opportunities for comprehensive control of HPV infections and related diseases” Vaccine Volume 30, Supplement X, 2012.

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“…Moreover, a recent study showed that glioma stem cells are resistant to proteasome inhibitors [173], further suggesting that proteasome inhibitors have only limited use in the radiotherapy of gliomas. However, the extent of sensitization of cells by proteasome inhibitors (possibly in combination) from cytotoxic agents may depend on the sequence of application [174] and the microenvironment [175]. Given the limited number of preclinical studies performed on this particularly challenging malignancy, it is too early to rule out the possibility that the right drug administration schedule, dose and optimal drug combinations could lead to potential improvement in glioma therapy.…”

Section: Marizomib In Preclinical Solid Tumor Modelsmentioning

confidence: 99%

Marizomib, a Proteasome Inhibitor for All Seasons: Preclinical Profile and a Framework for Clinical Trials

Potts¹,

Albitar²,

Anderson³

et al. 2011

CCDT

206

141

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The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade®) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique β-lactone-γ-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, che-motherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom’s macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid®), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside.

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The Proteasome Inhibitor MG-132 Protects Hypoxic SiHa Cervical Carcinoma Cells after Cyclic Hypoxia/Reoxygenation from Ionizing Radiation

Abstract: Proteasome inhibition radiosensitizes oxygenated tumor cells but may also protect tumor cells from ionizing radiation under certain hypoxic conditions.

Cited by 12 publications

References 28 publications

Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer

Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer

Therapy of Human Papillomavirus-Related Disease

Marizomib, a Proteasome Inhibitor for All Seasons: Preclinical Profile and a Framework for Clinical Trials

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