Survivin as a Preferential Target for Cancer Therapy

Abstract

Cancer is typically a consequence of imbalance between cell death and proliferation in a way favorable to cell proliferation and survival. Most conventional cancer therapies are based on targeting rapidly growing cancerous cells to block growth or enhance cell death, thereby, restoring the balance between these processes. In many instances, malignancies that develop resistance to current treatment modalities, such as chemotherapy, immunotherapy, and radiotherapy often present the greatest challenge in subsequent management of the patient. Studies have shown that under normal circumstances, cells utilize different death mechanisms, such as apoptosis (programmed cell death), autophagy, mitotic catastrophe, and necrosis to maintain homeostasis and physiological integrity of the organism, but these processes often appear to be altered in cancer. Thus, in recent years developing various strategies for administration of cytotoxic chemotherapeutics in combination with apoptosis-sensitizing reagents is receiving more emphasis. Here, we review the properties of the anti-apoptotic protein, survivin, a member of the inhibitor of apoptosis protein (IAP) family and the clinical feasibility and anti-cancer potential of drugs targeting this protein. We also discuss some key points and concerns that should be taken into consideration while developing drugs that target apoptotic proteins, such as survivin.

Silencing of survivin by YM155 induces apoptosis and growth arrest in hepatocellular carcinoma cells

“…The present study was limited to examination of the total apoptosis profile and the protein expression levels of procaspase-3, a principle 'executor', committing cells to death via the intrinsic apoptosis pathway (19,25). The results of the present study revealed that YM155 positively modulated the intrinsic apoptosis pathway and enhanced the total apoptosis ratios in HCC cells, which was consistent with the results of previous studies (18)(19)(20).…”

“…Apoptosis is a natural defense mechanism for the elimination of unhealthy cells, and the loss of sensitivity to apoptosis has been identified as a hallmark of cancer (6,(17)(18)(19). Accumulating evidence has revealed that survivin overactivation contributes to apoptotic dysfunction via the intrinsic and extrinsic apoptosis pathways (4,7,(17)(18)(19)(20).…”

“…In addition, survivin has demonstrated the ability to prevent the release of apoptosis-induced factor from the mitochondrial intermembrane space, protecting cells against apoptotic death (19,21,22). Futhermore, survivin also suppresses apoptosis via inhibition of the pathway of death receptors and downstream tumor necrosis factor-related apoptosis-inducing ligand (13,18,23,24). The present study was limited to examination of the total apoptosis profile and the protein expression levels of procaspase-3, a principle 'executor', committing cells to death via the intrinsic apoptosis pathway (19,25).…”

“…Accumulating evidence has revealed that survivin overactivation contributes to apoptotic dysfunction via the intrinsic and extrinsic apoptosis pathways (4,7,(17)(18)(19)(20). Given that survivin contains a single BIR domain, similarly to other IAP family members, it is not surprising that survivin is able to interfere with the activity of caspases in the mediation of apoptosis (18)(19)(20). In addition, survivin has demonstrated the ability to prevent the release of apoptosis-induced factor from the mitochondrial intermembrane space, protecting cells against apoptotic death (19,21,22).…”

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…49,50 Survivin participates to glioma radio-and chemotherapy resistance [50][51][52] and a selective inhibitor of survivin, YM155, is currently under clinical trials. [53][54][55] Beside the p53-dependent transcriptional control of survivin, other pathways including the PI3K/AKT or the integrin-linked kinase pathway driven by tyrosine kinase receptors or integrins 51,50,56 have been implicated in its regulation. Survivin is thus confirmed as a pertinent therapeutic target in GBM and strategies aiming to decrease its expression should be considered.…”