A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. IAPs
2.1. Anti-Apoptotic Mechanisms
2.1.1. Caspase Inhibition
2.1.2. Regulation of Survival Pathways
3. IAPs in Cancer
3.1. Acute Myeloid Leukemia (AML)
3.2. Chronic Lymphocytic Leukemia (CLL)
3.3. Colorectal Carcinoma
3.4. Breast Carcinoma
4. Smac Mimetics
4.1. Smac/DIABLO
4.2. Smac Mimetics
4.2.1. Smac Mimetics as Single Agents
4.2.2. The Role of TNF-α in the Efficacy of Smac Mimetics
4.2.3. The Role of Endoplasmic Reticulum (ER) Stress in IAP Inhibition
5. Combination Therapy
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Cancer Type | Observations | References |
---|---|---|
Acute Myeloid Leukemia (AML) | ||
XIAP | Lower levels of XIAP correlate with longer survival | Tamm et al. [48], Tamm et al. [49] |
No correlation between XIAP protein levels and survival | Carter et al. [50] | |
XIAP expression strongly correlates with cIAP1 and cIAP2 but no correlation with survivin was found. Low IAPs levels point to higher complete remission rate. | Pluta et al. [53] | |
Survivin | Appear to influence on the OS and it might be stronger than that from XIAP expression. | Pluta et al. [53] |
cIAP2 | High gene expression of cIAP2 is associated with poor OS | El-Mesallamy et al. [52] |
Livin | High level of Livin is correlated with poor OS | El-Mesallamy et al. [52] |
Childhood AML | ||
XIAP | High levels of XIAP positively correlate with risk groups, worse response to chemotherapy and shorter OS. | Tamm et al. [49] |
Livin | Livin negative patients showed longer OS in the acute promyelocytic AML | Zareifar et al. [55] |
Survivin | Survivin negative patients showed longer OS | Zareifar et al. [55] |
Apollon | Overexpression of apollon correlated with unfavorable prognosis. It was identified as a prognostic factor. | Ismail et al. [61], Sung et al. [60] |
Chronic Lymphocytic Leukemia | ||
XIAP | Higher expression of XIAP, cIAP1, cIAP2 and survivin was observed in patients with progressive disease which also exhibited inhibition of spontaneous apoptosis. | Grzybowska-Izydorczyk et al. [63] |
Modulation of XIAP expression sensitized CLL cells to chemotherapy in humans. | Zhu et al. [68] | |
Survivin | Co-expression of survivin and cIAP1 was related with shorter OS and identified as a negative prognostic factor. | Grzybowska-Izydorczyk et al. [63] |
Inhibition of survivin sensitized CLL cells to cytotoxic agents and induced apoptosis in and ex vivo model. | Purroy et al. [67] | |
Smac | Lower levels of Smac protein correlated with progressive disease. | Grzybowska-Izydorczyk et al. [63] |
Colorectal Carcinoma (CRC) | ||
Survivin | Survivin and cIAP2 expression was characteristic of elderly groups | Endo et al. [70] |
XIAP | XIAP expression was comparable in both normal and cancerous tissue of old and young patients. | Endo et al. [70] |
XIAP protein and mRNA levels are higher in cancerous tissue compared to surrounding normal tissue. | Lee et al. [74], Guoan et al. [75] | |
cIAPs | cIAP1 is most frequently expressed in nucleus while cIAP2 in the cytoplasm. A role of nuclear localization is suggested to be involved in the pathogenesis of CRC. | Ponnelle et al. [71] |
Higher cIAP2 levels are observed in stage II CRC either lymphoid metastasis and higher rate of chemotherapy failure with FU. | Karasawa et al. [72] | |
Together with TUCAN, cIAP2 low levels presented positive correlation with higher five-year survival. | Krajewska et al. [73] | |
Livin | Livin expression correlated with longer survival | Lee et al. [74] |
Apollon | Apollon was observed overexpressed in CRC tissue and correlated with unfavorable clinical features. | Bianchini et al. [77] |
Smac | Decreased expression of Smac was considered an independent factor for poor prognosis. | Endo et al. [78] |
Breast Carcinoma | ||
XIAP | XIAP and survivin expression was observed to be increased in advanced cancer. | Pluta et al. [80] |
Increased in XIAP expression was observed in higher grades of ductal invasive breast carcinoma and ductal breast carcinoma in situ. | Yang et al. [81] | |
High percentage of breast invasive ductal carcinoma with high immunoscore showed high XIAP expression. | Zhang et al. [82] | |
Higher cytoplasmic expression is observed compared to normal tissues and correlated with other molecular abnormalities. It was considered a prognostic biomarker. | Xu et al. [83] | |
High XIAP protein related with shorter OS | ||
cIAP2 | Levels were higher in node positive breast cancer | Pluta et al. [80] |
cIAP1 | cIAP1 levels did not correlate with clinicopathological features | Pluta et al. [80] |
Survivin | Correlated with metastasis, advanced stage and tumor size. | Youssef et al. [85] |
Positive expression of survivin have significant association with worse OS | Song et al. [88] | |
Livin | High expression is observed in high-invasive breast cancer cells compared to non-invasive cells. Authors described potential role in migration of cancer cells. | Li et al. [13] |
Smac | Lower expression was observed compared to healthy tissue | Pluta et al. [89] |
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Cetraro, P.; Plaza-Diaz, J.; MacKenzie, A.; Abadía-Molina, F. A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer. Cancers 2022, 14, 1671. https://doi.org/10.3390/cancers14071671
Cetraro P, Plaza-Diaz J, MacKenzie A, Abadía-Molina F. A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer. Cancers. 2022; 14(7):1671. https://doi.org/10.3390/cancers14071671
Chicago/Turabian StyleCetraro, Pierina, Julio Plaza-Diaz, Alex MacKenzie, and Francisco Abadía-Molina. 2022. "A Review of the Current Impact of Inhibitors of Apoptosis Proteins and Their Repression in Cancer" Cancers 14, no. 7: 1671. https://doi.org/10.3390/cancers14071671