Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central ...goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.
Survivin is a small protein that belongs to the inhibitor of apoptosis protein family. It is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor ...prognosis in many human neoplasms. This apoptotic inhibitor has a relevant role in both the promotion of cancer cell survival and in the inhibition of cell death. Consequently, aberrant survivin expression stimulates tumor progression and confers resistance to several therapeutic strategies in a variety of tumors. In fact, efficient survivin downregulation or inhibition results in spontaneous apoptosis or sensitization to chemotherapy and radiotherapy. Therefore, all these features make survivin an attractive therapeutic target to treat cancer. Currently, there are several survivin inhibitors under clinical evaluation, although more specific and efficient survivin inhibitors are being developed. Moreover, novel combination regimens targeting survivin together with other therapeutic approaches are currently being designed and assessed. In this review, recent progress in the therapeutic options targeting survivin for cancer treatment is analyzed. Direct survivin inhibitors and their current development status are explored. Besides, the major signaling pathways implicated in survivin regulation are described and different therapeutic approaches involving survivin indirect inhibition are evaluated. Finally, promising novel inhibitors under preclinical or clinical evaluation as well as challenges of developing survivin inhibitors as a new therapy for cancer treatment are discussed.
Survivin is a well-known inhibitor-of-apoptosis proteins family member and a promising molecular target for anti-cancer treatment. However, it is widely accepted that survivin is only a ...“semi-druggable” target and development of survivin-specific small molecule inhibitors has shown to be difficult. In this study, we demonstrated that a histidine-tagged survivin T34A-C84A mutated protein (T34A-C84A-dNSur-His) can be produced using a bacterial recombinant protein expression system E. coli ArcticExpress (DE3) cells and solubilized using 1% (w/v) Sarkosyl. In addition, we showed that the purified T34A-C84A-dNSur-His protein formed dimers as predicted by in silico protein structure and molecular dynamics analysis. Importantly, results of the MTT assay revealed that the purified recombinant protein was biologically active in decreasing the viability of the human MDA-MB-231 breast adenocarcinoma and MIA-PaCa pancreatic carcinoma cells in vitro. Furthermore, the purified T34A-C84A-dNSur-His protein, but not of the histidine-peptide, induced apoptosis (i.e. caspase-9 activation and DNA fragmentation) in MDA-MB-231 cells at concentrations from 50 to 400 nM. In conclusion, our study provides a protocol of producing a biologically active survivin-targeting macromolecule, T34A-C84A-dNSur-His, which can be used as a tool for studying the molecular and cellular roles of survivin in cells. T34A-C84A-dNSur-His is also a potential therapeutic agent for augmenting cancer therapy.
•Development of survivin-specific small molecule inhibitors as anticancer drugs is known to be difficult.•First report of successful purification of the recombinant survivin T34A-C84A mutated protein expressed in E. coli cells.•The purified recombinant survivin T34A-C84A protein is biologically active in promoting apoptosis in cancer cells.
Survivin is an inhibitor of apoptosis protein (IAP) that is highly expressed in many cancers and represents an attractive molecule for targeted cancer therapy. Although primarily regarded as an ...intracellular protein with diverse actions, survivin has also been identified in association with circulating tumor exosomes.
We have reported that active, specific vaccination with a long peptide survivin immunogen leads to the development of survivin-specific CD8-mediated tumor cell lysis and prolongation of survival in tumor-bearing mice. In addition to cellular antitumor responses, circulating anti-survivin antibodies are detected in the serum of mice and human glioblastoma patients following vaccination with the survivin immunogen.
Here we demonstrate that survivin is present on the outer cell membrane of a wide variety of cancer cell types, including both murine and human glioma cells. In addition, antibodies to survivin that are derived from the immunogen display antitumor activity against murine GL261 gliomas in both flank and intracranial tumor models and against B16 melanoma as well.
In addition to immunogen-induced, CD8-mediated tumor cell lysis, antibodies to the survivin immunogen have antitumor activity
Cell-surface survivin could provide a specific target for antibody-mediated tumor immunotherapeutic approaches.
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Hepatic fibrosis in injured liver is characterized by the activation of hepatic stellate cells (HSCs) from their quiescent state. Survivin (BIRC5) is one of the key genes that are upregulated during ...activation of HSCs but their role in HSC activation and fibrosis progression is unknown. Here, we have investigated the role of survivin protein in early fibrogenic activation of HSCs and fibrosis progression in chronic liver injury.
Primary quiescent HSCs were isolated from healthy mice liver through perfusion and cultured for fibrogenic activation. Survivin expression was suppressed by its pharmacological suppressant, YM155. We developed chronic liver injury induced fibrotic mice model through administrating repeated dose of CCl4 for 2 weeks and 4 weeks. Mice were pre-treated with YM155 a week before CCl4 administration till 2nd week of dosing and then discontinued. Hepatic parameters were characterized and underlying mechanisms were investigated.
Survivin expression gradually increased along with the expression of αSMA, collagen I activation maker in HSCs during their activation from quiescent state. Survivin suppression through YM155 downregulated αSMA, collagen I. Pre-treatment of YM155 in mice ceased the early activation of HSCs and onset of fibrosis in injured liver. However, discontinuation of YM155 initiated the activation of HSCs and fibrosis progression that shows survivin expression in HSCs is essential for their early activation and onset of liver fibrosis.
Survivin expression induces with activation of HSCs and drives onset of liver fibrosis in injured liver. Targeting survivin protein in activated HSCs could be a potential anti-fibrotic therapeutic approach in chronic liver injury.
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•Survivin expression induces with the activation of HSCs from their quiescent state.•Survivin inhibition in HSCs decreases αSMA and collagen I ex-vivo.•Survivin inhibition suppresses the onset of liver fibrosis.•Withdrawal of survivin suppression triggers the onset and progression of liver fibrosis.•Survivin expression is essential for early activation of HSCs and onset of liver fibrosis in injured liver.
Exosomes have shown increasing potential as delivery vesicles for therapy, but challenges like cost/yield, drug payload, and targeting specificity still exist. Plant derived exosome-like ...nanoparticles have been reported as a promising substitution and exhibit biocompatibility through oral, intranasal administration; however, systemic delivery of siRNA by exosome-like nanoparticles directly isolated from plants has not been reported. Recently, we reported the control of RNA orientation to decorate human derived exosome with cell targeting ligands for specific delivery of siRNA to tumors. Here, we expand to the application of arrowtail RNA nanoparticles for displaying ligands on ginger derived exosome-like nanovesicles (GDENs) for siRNA delivery and tumor inhibition through IV administration. Cushion ultracentrifugation coupled with equilibrium density gradient ultracentrifugation were used for purifying GDENs that displayed size, density, and morphology similar to human derived exosomes. Folic acid (FA), as a ligand, was displayed on the surface of GDENs for targeted delivery of survivin siRNA to KB cancer models. In vitro gene knockdown efficacy by FA-3WJ/GDENs/siRNA complex was comparable to transfection. We observed inhibition of tumor growth on a xenograft model by intravenous administration, which reveals the potential of GDENs as an economic delivery system for siRNA.
Melanoma is a type of skin cancer with an elevated incidence of metastasis and chemoresistance. Such features hamper treatment success of these neoplasms, demanding the search for new therapeutic ...options. Using a two-step resin-based approach, we recently demonstrated that cytotoxic prodiginines bind to the inhibitor of apoptosis protein, survivin. Herein, we explore the role of survivin in melanoma and whether its modulation is related to the antimelanoma properties of three cytotoxic prodiginines (prodigiosin, cyclononylprodigiosin, and nonylprodigiosin) isolated from marine bacteria. In melanoma patients and cell lines, survivin is overexpressed, and higher levels negatively impact survival. All three prodiginines caused a decrease in cell growth with reduced cytotoxicity after 24 h compared to 72 h treatment, suggesting that low concentrations promote cytostatic effects in SK-Mel-19 (BRAF mutant) and SK-Mel-28 (BRAF mutant), but not in SK-Mel-147 (NRAS mutant). An increase in G1 population was observed after 24 h treatment with prodigiosin and cyclononylprodigiosin in SK-Mel-19. Further studies indicate that prodigiosin induced apoptosis and DNA damage, as detected by increased caspase-3 cleavage and histone H2AX phosphorylation, further arguing for the downregulation of survivin. Computer simulations suggest that prodigiosin and cyclononylprodigiosin bind to the BIR domain of survivin. Moreover, knockdown of survivin increased long-term toxicity of prodigiosin, as observed by reduced clonogenic capacity, but did not alter short-term cytotoxicity. In summary, prodiginine treatment provoked cytostatic rather than cytotoxic effects, cell cycle arrest at G0/G1 phase, induction of apoptosis and DNA damage, downregulation of survivin, and decreased clonogenic capacity in survivin knockdown cells.
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•Survivin is overexpressed in melanoma cell lines and melanoma patients ‘samples.•Treatment with prodiginines exhibits cytotoxicity against melanoma cells.•Prodigiosin causes DNA damage, cell cycle arrest and survivin downregulation.•Computer simulations show prodiginines bind to BIR domain of survivin.•Survivin knockdown increased long-term toxicity of prodigiosin in melanoma cells.
DHA downregulated Mcl-1 and Survivin by targeting the JAK2-STAT3 signaling pathway and upregulating Bim, thereby synergizing with ABT-263 to trigger apoptosis in NSCLC cells harboring EGFR or RAS ...mutation.
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Non-small cell lung cancer (NSCLC) is the most common malignancy worldwide. A significant fraction of NSCLC carries activating mutations in epidermal growth factor receptor (EGFR) or RAS oncogene. Dihydroartemisinin (DHA) is a semisynthetic derivative of the herbal antimalarial drug artemisinin that has been recently reported to exhibit anti-cancer activity. To develop new therapeutic strategies for NSCLC, we investigated the interactions between DHA and ABT-263 in NSCLC cells harboring EGFR or RAS mutation. Our data indicated that DHA synergized with ABT-263 to trigger Bax-dependent apoptosis in NSCLC cells in culture. DHA treatment antagonized ABT-263-induced Mcl-1 upregulation and sensitized NSCLC cells to ABT-263-triggered apoptosis. Additionally, DHA treatment caused downregulation of Survivin and upregulation of Bim, which also contribute to cotreatment-induced cytotoxicity. Moreover, DHA effectively suppressed STAT3 phosphorylation, and STAT3 inactivation resulted in the downregulation of Mcl-1 and Survivin, functioning to enhance ABT-263-induced cytotoxicity. Finally, cotreatment of DHA and ABT-263 significantly inhibited xenograft growth in nude mice. Together, DHA effectively inhibits STAT3 activity and modulates expression of Mcl-1, Survivin and Bim, thereby synergizing with ABT-263 to trigger apoptosis in NSCLC cells harboring EGFR or RAS mutation. Our data provide a novel therapeutic strategy for EGFR or RAS mutant NSCLC treatment.
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