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.
Available from: Lin Zhang
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ABSTRACT: Second mitochondria-derived activator of caspase (Smac) regulates chemotherapy-induced apoptosis. Smac mimetics have been tested in clinical trials as chemosensitizers. We determined the role of Smac in modulating the chemosensitivity of esophageal squamous cell carcinoma (ESCC).
Smac expression was evaluated in tissues from ESCC patients with differential chemotherapeutic responses. The effects of Smac knockdown and Smac mimetics on the chemosensitivity of ESCC cells and the molecular mechanisms by which Smac and Smac mimetics modulate chemosensitivity were determined. The therapeutic responses of ESCC cells with different Smac statuses were compared using xenograft models.
We found that Smac was significantly downregulated in most ESCC samples (36.8%, 25/68, P = 0.001), and Smac expression differed significantly (P < 0.05) between chemosensitive and chemoresistant tumors. The associations of tested factors and their responses were examined using logistic regression analysis. In ESCC cells treated with cisplatin, a common chemotherapeutic drug, Smac and cytochrome c were released from mitochondria, and caspase-3 and caspase-9 were activated. Knockdown of Smac abrogated cisplatin-induced apoptosis, mitochondrial dysfunction, cytochrome c release, and caspase activation. Smac deficiency also reduced the effect of cisplatin on long-term cell viability, and led to cisplatin resistance in xenograft tumors in vivo. LBW242, a small molecule Smac mimetic, enhanced cisplatin-induced apoptosis and caspase activation and restored cisplatin sensitivity in Smac-deficient cells.
Our data suggested that downregulation of Smac may be a chemoresistance mechanism in ESCC. Combinations of Smac mimetics with chemotherapeutic agents may have therapeutic benefits for the treatment of esophageal cancer.
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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.
Available from: Liang Xu
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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.
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