Prognostic value of Smac expression in rectal cancer patients treated with neoadjuvant therapy
Department of Radiation Oncology, Shandong Tumor Hospital, Jinan 250117, China.Medical Oncology (Impact Factor: 2.63). 03/2011; 29(1):168-73. DOI: 10.1007/s12032-011-9819-x
The objective was to evaluate expression of second mitochondria-derived activator of caspase (Smac) expression before and after treatment in patients treated with preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer and to correlate the clinicopathological characteristics and level of Smac expression with pathologic response and outcome. Expression of biomarker was evaluated by immunohistochemistry in tumor samples from 98 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy plus concurrent chemotherapy. All patients received a standardized total mesorectal excision procedure after a long interval of 4-6 weeks. For Smac, patients with a good response to neoadjuvant CRT tended to have higher pre-therapy levels (P = 0.007). The level of Smac expression decreased after neoadjuvant therapy (P = 0.016). High expression of Smac before CRT, and high Dworak's tumor regression grade (TRG) were significantly associated with improved 5-year disease-free survival (P < 0.05). Pretreatment nodal status also was significantly associated with 5-year disease-free survival and 5-year local relapse-free survival (P < 0.05). Multivariate analysis confirmed that the pretreatment expression of Smac and Lymph nodal status were independent prognostic factors. Our study suggests that high expression of Smac before neoadjuvant CRT could predict good outcome in locally advanced rectal cancer patients.
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ABSTRACT: Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.Nature Reviews Drug Discovery 02/2012; 11(2):109-24. DOI:10.1038/nrd3627 · 41.91 Impact Factor
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ABSTRACT: The majority of chemo/radiotherapies inhibit cancer cell growth by activating cell death pathways, such as apoptosis, necrosis, and autophagy-associated cell death. However, as the disease progresses, cancer cells can acquire a variety of genetic and epigenetic alterations, which leads to dysregulation of cell death-associated signaling pathways and chemo/radioresistance. Designing novel drugs and enhancing therapeutic strategies to improve survival and quality of life for cancer patients must specifically target pathways responsible for drug resistance. Two cellular mechanisms can contribute to chemo/radioresistance: inhibition of apoptotic cell death pathways and induction of autophagy, a cell survival response. The development of novel drugs and extensive research studies has provided significant insight into the aberrant regulation of apoptosis and key apoptosis inhibitor proteins during tumorigenesis. However, the extensive dysregulation of cell growth pathways in cancer cells makes it necessary to target multiple pathways in order to elicit a lasting death response. Autophagy, classically designated as a cell “survival” mechanism, appears to play a greater role in cell death than previously conceived. This contradiction between autophagy-associated cell survival versus cell death has intensified the interest in this field of research in cancer therapeutics. Understanding how autophagic cells cross the threshold from cell survival to cell death during drug treatments is imperative for identifying more potent therapies. Utilizing novel treatments that will re-activate apoptotic cell death pathways, while driving autophagy-associated cell death will lead to more effective chemotherapies, thereby enhancing overall patient survival.Apoptosis, 05/2013: pages 155-196; InTech.
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ABSTRACT: Lack of apoptosis is a key factor in carcinogenesis and tumor progression. Survivin is a member of the inhibitor of apoptosis protein (IAP) family. Second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) is an antagonist of IAPs. Recently, Smac/DIABLO was identified as a potent therapeutic target. However, the clinical significance of Smac/DIABLO in gastrointestinal carcinomas remains unclear. In the present study, Smac/DIABLO expression was analyzed by immunohistochemistry in 72 gastric adenocarcinomas and 78 colorectal adenocarcinomas. The expression of Smac/DIABLO was significantly higher in colorectal carcinoma than in gastric carcinoma. Additionally, a correlation was found between the expression of Smac/DIABLO and nuclear survivin in well- to moderately-differentiated colorectal adenocarcinomas (r=0.245; P<0.01). Based on these results, it was hypothesized that gastric and colorectal carcinomas differ in the level of Smac/DIABLO expression. Our previous studies revealed that the expression of cleaved caspase-9 was significantly lower in colorectal carcinoma than in gastric carcinoma (P<0.0001). Conversely, the expression levels of microtubule-associated protein 1 light chain 3 (LC3), an autophagy marker, and survivin were significantly higher in colon cancer than in gastric cancer (P<0.0001 and P<0.01, respectively). Taken together, these results indicate that not only LC3 and survivin expression, but also Smac/DIABLO expression, are significantly higher in colorectal carcinoma than in gastric carcinoma. We hypothesize that the analysis of Smac/DIABLO, survivin and LC3 expression in colorectal carcinoma is likely to aid cancer therapy due to the involvement of these markers in apoptosis and/or autophagy.Oncology letters 12/2014; 8(6):2581-2586. DOI:10.3892/ol.2014.2598 · 1.55 Impact Factor
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