ABT-737 Synergizes with Chemotherapy to Kill Head and Neck Squamous Cell Carcinoma Cells via a Noxa-Mediated Pathway

Li, Rongxiu; Zang, Yan; Li, Changyou; Patel, Neil; Grandis, Jennifer R.; Johnson, Daniel E.

doi:10.1124/mol.108.052969

Cited by 55 publications

(44 citation statements)

References 40 publications

(75 reference statements)

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“…3A). The effect of Noxa siRNA was reproducibly observed and its magnitude was comparable to that was previously found with various cell types including CLL cells (13,14,(33)(34)(35). Consequently, loss of Noxa expression reduces partially hyperforin-induced apoptosis, indicating that the BH3-only protein mediates in part this apoptosis induction and that at least another mechanism is involved.…”

Section: Noxa Silencing Reduces Hyperforin-induced Apoptosissupporting

confidence: 62%

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Billard

2011

Int J Oncol

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Abstract. We previously reported that hyperforin, a phloroglucinol purified from Hypericum perforatum, induces the mitochondrial pathway of caspase-dependent apoptosis in chronic lymphocytic leukemia (CLL) cells ex vivo, and that this effect is associated with upregulation of Noxa, a BH3-only protein of the Bcl-2 family. Here, we investigated the role of this upregulation in the pro-apoptotic activity of hyperforin in the cells of CLL patients and MEC-1 cell line. We found that the increase in Noxa expression is a time-and concentrationdependent effect of hyperforin occurring without change in Noxa mRNA levels. A post-translational regulation is suggested by the capacity of hyperforin to inhibit proteasome activity in CLL cells. Noxa silencing by siRNA reduces partially hyperforin-elicited apoptosis. Furthermore, treatment with hyperforin, which has no effect on the expression of the prosurvival protein Mcl-1, induces the interaction of Noxa with Mcl-1 and the dissociation of Mcl-1/ Bak complex, revealing that upregulated Noxa displaces the proapoptotic protein Bak from Mcl-1. This effect is accompanied with Bak activation, known to allow the release of apoptogenic factors from mitochondria. Our data indicate that Noxa upregulation is one of the mechanisms by which hyperforin triggers CLL cell apoptosis. They also favor that new agents capable of mimicking specifically the BH3-only protein Noxa should be developed for apoptosis-based therapeutic strategy in CLL.

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Section: Noxa Silencing Reduces Hyperforin-induced Apoptosissupporting

confidence: 62%

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Billard

2011

Int J Oncol

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“…Our initial identification of Bcl2 as a biomarker in OPSCC arose from our studies of the cellular mechanisms underlying apoptosis resistance in HNSCC cell lines (13). High levels of Bcl2 expression provide cisplatin resistance to such cell lines (13,28) and the well-known antiapoptotic effects of Bcl2 presumably underlie its association with worse outcome in primary radiotherapy of laryngeal cancer (29). The antiapoptotic mechanisms of Bcl2 and related antiapoptotic proteins are well enough understood that Bcl2 family inhibitors are being evaluated in clinical trials (27).…”

Section: Discussionmentioning

confidence: 99%

Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer

Nichols

Finkelstein

Faquin

et al. 2010

Clinical Cancer Research

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Purpose: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papilloma virus (HPV) is rapidly growing in incidence. Despite better prognosis than OPSCC associated with traditional risk factors, treatment failure still occurs in a significant proportion of patients. We had identified the antiapoptotic protein Bcl2 as a marker for poor outcome in advanced OPSCC treated with concurrent chemoradiation. To determine whether Bcl2 and HPV together might further characterize treatment response, we examined whether the prognostic value of Bcl2 was independent of HPV status.Experimental Design: Pretreatment tumor biopsies from 68 OPSCC patients were tested for HPV by in situ hybridization and were immunostained for Bcl2 to evaluate relations with disease-free (DFS) and overall survival following platin-based concurrent chemoradiation. Median follow-up among surviving patients was 47 months (range, 10-131 months).Results: Bcl2 and HPV independently predicted DFS and overall survival. Hazard ratios (with 95% confidence interval) for positive versus negative status in bivariate Cox proportional hazard analysis of DFS were 6.1 (1.8-21) for Bcl2 and 0.11 (0.035-0.37) for HPV. Only 1 of 32 HPV-positive/Bcl2-negative tumors recurred. Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the <40% of patients whose primary tumors were Bcl2 positive.Conclusions: Independent of HPV status, pretreatment Bcl2 expression identifies a subset of OPSCC patients having increased risk of treatment failure, particularly through distant metastasis, after concurrent chemoradiation. Considering HPV and Bcl2 together should help in devising better personalized treatments for OPSCC. Clin Cancer Res; 16(7); 2138-46. ©2010 AACR.Patients with human papillomavirus (HPV)-related tumors represent an increasing fraction of newly diagnosed squamous cell carcinomas of the head and neck (HNSCC; refs. 1, 2). These tumors, almost solely oropharyngeal squamous cell carcinomas (OPSCC), typically present at an advanced stage by traditional tumor-node-metastasis (TNM) criteria, yet respond better to treatment than do tumors associated with traditional risk factors (3-11). Nevertheless, a significant fraction of HPV-related tumors resist current standards of care, so it is important to find additional ways to determine prognosis and guide therapy.Cellular mechanisms inhibiting apoptosis can contribute to poor treatment outcome. In HNSCC cell lines, we found that high expression of the antiapoptotic protein Bcl2 enhanced tumor-cell survival, in particular after treatment with cisplatin (12, 13). We extended these findings to advanced OPSCC treated with platinum-based concurrent chemoradiation, a current standard of care (9,14,15), and determined that high pretreatment tumor expression of Bcl2 predicted worse clinical outcome (13).These findings suggest that considering HPV and Bcl2 together might further classify OPSCC with respect to therapeutic response. To evaluate th...

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“…ABT-737 has shown preclinical anticancer activity as a single agent or in combination with other chemotherapeutic agents against acute myeloid leukemia (AML; refs. 20,21), multiple myeloma (22), lymphoma (23,24), chronic lymphocytic leukemia (25), small-cell lung cancer (19,26), head and neck squamous cancer (27), and acute lymphoblastic leukemia (1,28). Given that ABT-737 binds to Mcl-1 with low affinity, the high basal expressions of Mcl-1 in small-cell lung cancer cells (29,30) and in other types of cancer cells (19,31) have been validated to associate with the resistance to ABT-737 (24).…”

Section: Introductionmentioning

confidence: 99%

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Zhang

Cai

Zhu

et al. 2011

Molecular Cancer Therapeutics

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The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL, but not Mcl-1, which may confer resistance to this agent in various cancers with high levels of Mcl-1. Here, we showed that the combination of gemcitabine and ABT-737 exhibited synergistic cytotoxicity and induced significant apoptosis in multiple cancer types, including lung, renal, bladder, and prostate cancers. The enhanced apoptosis induced by gemcitabine plus ABT-737 was accompanied by the greater extent of mitochondrial depolarization, caspases-3 activation, and PARP cleavage in 95-D and 5637 cell lines. Importantly, in ABT-737-resistant cancer cells, the interaction between USP9X and Mcl-1, which was increased by ABT-737 treatment, could be disrupted by gemcitabine, thus resulting in enhanced ubiquitination and the subsequent degradation of Mcl-1 and ultimately in the synergism of these two drugs. Moreover, the increased anticancer efficacy of gemcitabine combined with ABT-737 was further validated in a human lung cancer 95-D xenograft model in nude mice. Taken together, our data first showed the synergistic anticancer capabilities achieved by combining gemcitabine and ABT-737 and, second, opened new opportunities to use antiapoptotic Bcl-2 family members, which drive tumor cell resistance in current anticancer therapies, therapeutically. Mol Cancer Ther; 10(7); 1264-75. Ó2011 AACR.

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ABT-737 Synergizes with Chemotherapy to Kill Head and Neck Squamous Cell Carcinoma Cells via a Noxa-Mediated Pathway

Cited by 55 publications

References 40 publications

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Bcl2 and Human Papilloma Virus 16 as Predictors of Outcome following Concurrent Chemoradiation for Advanced Oropharyngeal Cancer

Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

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