Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma

“…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).…”

mentioning

confidence: 76%

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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“…For instance, conclusive clinical data on the association between the proapoptotic BCL-2 family members BAX and BAK and cisplatin sensitivity are missing, but elevated levels of their antiapoptotic counterparts including BCL-2, BCL-X L and MCL-1 (myeloid cell leukemia sequence 1) reportedly correlate with cisplatin resistance and tumor recurrence in multiple clinical scenarios, including head and neck cancer, ovarian cancer and NSCLC (Han et al, 2003;Erovic et al, 2005;Williams et al, 2005;Michaud et al, 2009). Moreover, ongoing clinical trials are evaluating the combination of cisplatin with small molecules that inhibit BCL-2-like proteins (for example, ABT-263, ABT-737) for the treatment of several neoplasms (Jain and MeyerHermann, 2011).…”

Section: Chemoresistance To Cisplatin L Galluzzi Et Almentioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Bcl-2 Blocks Cisplatin-Induced Apoptosis and Predicts Poor Outcome Following Chemoradiation Treatment in Advanced Oropharyngeal Squamous Cell Carcinoma

Cited by 109 publications

References 44 publications

A Novel Selenadiazole Derivative Induces Apoptosis in Human Glioma Cells by Dephosphorylation of AKT

A Novel Selenadiazole Derivative Induces Apoptosis in Human Glioma Cells by Dephosphorylation of AKT

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

Molecular mechanisms of cisplatin resistance

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