Abstract
Survivin, an anti-apoptotic molecule abundantly expressed in most human neoplasms, has been reported to contribute to cancer initiation and drug resistance in a wide variety of human tumors. Efficient downregulation of survivin can sensitize tumor cells to various therapeutic interventions, generating considerable efforts in its validation as a new target in cancer therapy. This review thoroughly analyzes up-to-date information on the potential of survivin as a therapeutic target for new anticancer treatments. The literature dealing with the therapeutic targeting of survivin will be reviewed, discussing specifically squamous cell carcinomas (SCCs), and with emphasis on the last clinical trials. This review gives insight into the recent developments undertaken in validating various treatment strategies that target survivin in SCCs and analyze the translational possibility, identifying those strategies that seem to be the closest to being incorporated into clinical practice. The most recent developments, such as dominant-negative survivin mutants, RNA interference, anti-sense oligonucleotides, small-molecule inhibitors, and peptide-based immunotherapy, seem to be helpful for effectively downregulating survivin expression and reducing tumor growth potential, increasing the apoptotic rate, and sensitizing tumor cells to chemo- and radiotherapy. However, selective and efficient targeting of survivin in clinical trials still poses a major challenge.
Highlights
Most squamous cell carcinomas (SCCs) cases are included in four categories: head and neck squamous cell carcinoma (HNSCC), esophageal cancer, non-melanoma skin cancer, and non-small cell lung cancer (NSCLC) [1,2]
Regarding oral squamous cell carcinoma (OSCC), in our previous studies we found that survivin is expressed in about 80% of this tumor type, and that its degree of expression is directly related to an aggressive phenotype [83,85,92,93]
There are several studies addressing the use of miRNAs as anticancer therapy; some have evaluated the possibility of silencing survivin gene expression, inducing apoptosis, and inhibiting cell growth, in the HeLa cell line [124,125]
Summary
The term “squamous cell carcinoma” (SCC) is used to indicate a heterogeneous group of different epithelial malignancies that arise from uncontrolled growth of epithelial cells [1]. From the point of view of anticancer therapy, the multiple functions performed by survivin in molecular processes that are typically altered in cancer cells suggest that targeting survivin may be advantageous compared with targeting other molecules involved in a single oncogenic pathway [98] This protein intersects multiple cellular network and disabling it can compromise multiple signaling networks required for tumor cell maintenance, bypassing the ability to elicit resistance through mutations by cancer cells [99]. Survivin expression is regulated by developmental signaling pathways that sustain stem cells, suggesting the possibility of using survivin antagonists with the aim of affecting cancer stem cells [100] Another advantage is that this protein is highly expressed in endothelial cells during the proliferative phase of angiogenesis; it has a direct role in tumor angiogenesis and carcinogenesis [38,39,43]. Since most cytotoxic agents currently in use induce apoptosis of cancer cells and survivin upregulation seems to play a pivotal role in resistance to chemo- and radiotherapy [24,101], new classes of targeted drugs are emerging based on strategies to inhibit the expression or function of survivin
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