Influence of high expression of Smac/DIABLO protein on the clinical outcome in acute myeloid leukemia patients

Pluta, Agnieszka; Wrzesień‐Kuś, Agata; Cebula-Obrzut, Barbara; Wolska, Anna; Szmigielska-Kapłon, Anna; Czemerska, Magdalena; Pluta, Piotr; Robak, Tadeusz; Smolewski, Piotr; Wierzbowska, Agnieszka

doi:10.1016/j.leukres.2009.11.030

Cited by 25 publications

(17 citation statements)

References 27 publications

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“…69 Also, there was a correlation of low protein levels of Smac and poor karyotype in the same patient cohort. 69 Analysis of Smac protein expression by immunohistochemistry in Hodgkin's lymphoma and non-Hodgkin's lymphoma tumor samples showed that Smac is expressed in a large proportion of Hodgkin's lymphoma (25/40 ¼ 63%) and non-Hodgkin's lymphoma (117/247 ¼ 47%). 70 It is interesting to note that Smac displayed a differential expression in distinct subtypes of non-Hodgkin's lymphoma.…”

Section: Smac/diablo In Hematological Malignanciesmentioning

confidence: 66%

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Fulda

2012

Leukemia

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Resistance to apoptosis is one of the hallmarks of human cancers and contributes to the insensitivity of many cancers to commonly used treatment approaches. Inhibitor of apoptosis (IAP) proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and promote survival. High expression of IAP proteins is observed in multiple cancers, including hematological malignancies, and has been associated with unfavorable prognosis and poor patients' outcome. Therefore, IAP proteins are currently considered as promising molecular targets for therapy. Indeed, drug-discovery approaches over the last decade aiming at neutralizing IAP proteins have resulted in the generation of small-molecule inhibitors or antisense oligonucleotides that demonstrated in vitro and in vivo antitumor activities in preclinical studies. As some of these strategies have already entered the stage of clinical evaluation, for example, in leukemia, an update on this promising molecular-targeted strategy to interfere with apoptotic pathways is of broad interest.

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Section: Smac/diablo In Hematological Malignanciesmentioning

confidence: 66%

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Fulda

2012

Leukemia

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“…The lowest expression, about 20%, was seen in prostate cancer patients [9]. With regard to hematological malignancies, expression of Smac/DIABLO was confirmed in almost all (96%) acute myeloid leukemia patients (15). Ren et al found this protein in 63% of Hodgkin lymphoma patients and only in 47% of non-Hodgkin lymphoma patients (16).…”

Section: Discussionmentioning

confidence: 99%

Correlation of Smac/DIABLO protein expression with the clinico-pathological features of breast cancer patients

Pluta¹,

Cebula-Obrzut²,

Ehemann³

et al. 2011

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Smac/DIABLO protein promotes caspase-dependent apoptosis by inhibition of inhibitor of apoptosis protein (IAP) family members. The role of Smac/DIABLO in breast cancer has not been yet established. Therefore, the aim of the study was to assess the expression of this protein in tumor cells from breast cancer patients. The expression of Smac/DIABLO was analyzed in 62 breast cancer patients by flow cytometry. The obtained results were compared with expression of this protein in benign breast tumor tissue, which served as the control (11 patients with fibroadenoma). Expression of caspase-3 proteins in breast cancer was also evaluated. Smac/DIABLO expression in breast cancer was correlated with clinical and pathological data. Although the expression of Smac/DIABLO protein was found in all examined samples of both the breast cancer and fibroadenoma patients, the median expression of Smac/Diablo in breast cancer was significantly lower than in the control (39.1% vs. 48.1%; p=0.0047). Smac/DIABLO expression correlated with expression of caspase-3 (p=0.000008). In pT1 breast cancer patients, expression of Smac/DIABLO protein was higher than in those with pT2-3 (p=0.02). Diffuse cancer infiltration significantly correlated with lower expression of Smac/DIABLO protein (p=0.02). Moreover, there was a loose correlation between low expression of Smac/DIABLO protein and cancer embolus in minor blood and lymphatic vessels (p=0.08). Our results indicate that expression of Smac/DIABLO inversely correlates with the tumor stage, which may suggest that this protein may play an important role in the breast cancer development.

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“…SMAC has been a target for drug development because expression of SMAC at low levels has been correlated with poor prognosis in solid tumors [141–143]. In AML, high expression of SMAC has been correlated with longer overall survival and higher complete remission rates [144]. The crystal structure of SMAC complexed with XIAP has been solved [145–147].…”

Section: Targeting the Apoptosis Pathwaymentioning

confidence: 99%

Targeting the apoptosis pathway in hematologic malignancies

Zaman¹,

Wang²,

Gandhi³

2014

Leukemia & Lymphoma

186

146

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Apoptosis is a cell death program that is well-orchestrated for normal tissue homeostasis and for removal of damaged, old, or infected cells. It is regulated by intrinsic and extrinsic pathways. The intrinsic pathway responds to signals such as ultraviolet radiation or DNA damage and activates “executioner” caspases through a mitochondria-dependent pathway. The extrinsic pathway is activated by death signals induced, for example, by an infection that activates the immune system or receptor-mediated pathways. The extrinsic pathway signals also cascade down to executioner caspases that cleave target proteins and lead to cell death. Strict control of cellular apoptosis is important for the hematopoietic system as it has a high turnover rate. However, the apoptosis program is often deregulated in hematologic malignancies leading to the accumulation of malignant cells. Therefore, apoptosis pathways have been identified for development of anticancer therapeutics. We review here the proteins that have been targeted for anticancer drug development in hematologic malignancies. These include BCL-2 family proteins, death ligands and receptors, inhibitor of apoptosis family proteins, and caspases. Except for caspase activators, drugs that target each of these classes of proteins have advanced into clinical trials.

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Influence of high expression of Smac/DIABLO protein on the clinical outcome in acute myeloid leukemia patients

Cited by 25 publications

References 27 publications

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

Correlation of Smac/DIABLO protein expression with the clinico-pathological features of breast cancer patients

Targeting the apoptosis pathway in hematologic malignancies

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