Survivin is highly expressed in a broad range of solid tumors and hematological malignancies. Increased survivin expression in cancer patients is an unfavorable prognostic marker correlating with decreased overall survival in several malignancies, including non-small cell lung [24–26], gastric [27–31], colorectal [32–34], and breast carcinomas , neuroblastoma , prostate cancer , pancreatic cancer  , hepatocellular carcinoma  and hematologic malignancies [40–44]. Increased survivin expression was also associated with increased risk of recurrence, lymph node invasion and metastasis. Finally, survivin overexpression may be a predictive factor to determine response to chemotherapy and radiotherapy in patients with bladder cancer, breast cancer, multiple myeloma and lymphoma. Studies have shown that survivin suppression induces tumor cell apoptosis and enhances sensitivity to apoptosis induced by existing anticancer drugs and other apoptotic stimuli. This work indicated that survivin also be an important target for human Wilms tumor cells.
YM155 is a novel survivin suppressant that is currently in clinical development by Astellas Pharma, Inc. YM155 inhibited the growth of 119 human cancer cell lines, with the greatest activity in lines derived from non-Hodgkin’s lymphoma, hormone-refractory prostate cancer, ovarian cancer, sarcoma, non-small-cell lung cancer, breast cancer, leukemia and melanoma. The mean log growth inhibition of 50% (GI50) value was 15 nM. A preclinical study showed that YM155 suppressed both survivin protein and mRNA expression. In a toxicologic study, short-term exposure at high blood concentrations caused cardiotoxicity in the form of atrioventricular. In this phase I study, YM155 seemed to be safe and well-tolerated, with a maximum tolerated dose of 8.0 mg/m2/d. Stable disease was achieved in nine patients. The data in this study indicate that the adverse reactions observed can be well-controlled by taking due caution and suggest that YM155 has more easily controllable toxicities compared with conventional cytotoxic anticancer drugs. This work also supports the view that YM155 had significant role and little side effect in the treatment of SK-NEP-1 xenograft tumors.
Real-time PCR Array System is the ideal tool for analyzing the expression of a focused panel of genes. The flexibility, simplicity, and convenience of standard SYBR Green PCR detection methodology make the PCR Array System accessible for routine use in any research laboratory . In this study, we analyzed the dyes-regulated genes by YM155 with this powerful platform, Real-time PCR arrays.
Comparison of PCR results between Test group and control group showed that 32 genes were significantly up-regulated and 54 genes were significantly down-regulated after YM155 treatment. Some genes, such as TNF, NFKB1, CDKN1A, CASP9, COL4A3, BIRC5 (survivin), BCL2, and DAPK1 have already been reported with YM155 treatment. There are also some other genes never reported with YM155 treatment and these genes have complicate functions far exceeds the apoptosis. These results consistent with the complicate roles of survivin in cancer biology. Survivin has been implicated in the regulation of the mitotic spindle checkpoint, from kinetic core to spindle assembly; it’s over expression in cancer may allow cells with spindle defects or misaligned kinetic cores to continue through cell division. Recent studies also suggest that survivin plays a role in tumor progression and chemoresistance. Survivin has been shown to inhibit cell death induced by several anticancer agents, including paclitaxel , etoposide  and Tumor Necrosis Factor-a related apoptosis-inducing ligand [47, 48]. In vitro and in vivo studies showed that inhibiting survivin reduces tumor growth potential and sensitizes tumor cells to chemotherapeutic agents, such paclitaxel, cisplatin [14, 49], etoposide, gamma irradiation and immunotherapy. To explore the molecule mechanism of YM155 treatment, we try to explore new target and “net work” of YM155 with a powerful platform, Ingenuity Pathway Analysis program.
The basis of the IPA program consists of the Ingenuity Pathway Knowledge Base (IPKB) which is derived from known functions and interactions of genes published in the literature. The IPA Tool allows the identification of biological networks, global functions and functional pathways of a particular dataset. The program also gives the significance value of the genes, the other genes with which it interacts, and how the products of the genes directly or indirectly act on each other, including those not involved in the microarray analysis. This work represents cell death was the highest rated network with 65 focus molecules and the significance score of 44. Death receptor signaling, TNFR1 signaling ,induction of apoptosis by HIV1 ,apoptosis signaling and molecular mechanisms of cancer came out to be the top four most significant pathways. IPA analysis also showed top molecules up-regulated was BBC3 (PUMA). PUMA encodes a member of the BCL-2 family of proteins. This family member belongs to the BH3-only pro-apoptotic subclass. The protein cooperates with direct activator proteins to induce mitochondrial outer membrane permeabilization and apoptosis. It can bind to anti-apoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. Because of its pro-apoptotic role, this gene is a potential drug target for cancer therapy and for tissue injury. IPA analysis also showed upstream regulators were NR3C1, TP53, dexamethasone, TNF and Akt. These upstream regulators such as TP53, TNF and Akt have already been reported as important regulators for the survivin network. TP53 and Akt have been widely investigated and there are hundreds of papers about the important roles in survivin pathway. But there is still no report about the relationship between NR3C1, dexamethasone and survivin. NR3C1 gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Dexamethasone gene encodes a member of the Ras superfamily of small GTPases and is induced by dexamethasone. The encoded protein is an activator of G-protein signaling and acts as a direct nucleotide exchange factor for Gi-Go proteins. This protein interacts with the neuronal nitric oxide adaptor protein CAPON, and a nuclear adaptor protein FE65, which interacts with the Alzheimer's disease amyloid precursor protein. This gene may play a role in dexamethasone-induced alterations in cell morphology, growth and cell-extracellular matrix interactions. Epigenetic inactivation of this gene is closely correlated with resistance to dexamethasone in multiple myeloma cells. This work indicated firstly that NR3C1and dexamethasone may be upstream regulators in the survivin pathway. These results may provide new clues of molecular mechanism of apoptosis induced by YM155.