Phox2B correlates with MYCN and is a prognostic marker for neuroblastoma development. as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma. mutation with multidrug resistance. 158 3.1.3. Baculoviral IAP repeat containing 5 (BIRC5) and survivin inhibitors The BIRC5 gene encodes human survivin, which is located on the long arm of chromosome 17 (q25). 159 Advanced\stage NB often exhibits a gain of the chromosomal 17q25 region, 160 and the BIRC5 gene (present in this 17q25 region) is gained in 49% of NB tumors. 161 Increased survivin expression is correlated with a poor prognosis in NB patients. 160 In fact, the levels of survivin mRNA are higher in individuals older than 12 months, in advanced stages of disease (stages 3 and 4), and have a strong correlation with low levels of TrkA expression. 160 The elevated levels of survivin expression in NB are also correlated with MYCN amplification. 160 Survivin also increases glycolysis and resistance to treatment in NB. 162 , 163 In addition, survivin exerts antiapoptotic effects by inhibiting caspase 9 and enhancing resistance to apoptosis induced by staurosporine in NB cells. 164 Survivin has also been found to provide resistance to immune\ or drug\mediated cell death. 165 For example, a study of several NB cell lines has found that NB10, NB cell line that exhibits the least survivin expression, was the most sensitive to both TRAIL (tumor necrosis factor [TNF]\related apoptosis\inducing ligand) and etoposide induced cell death. 165 On the contrary, the NB7 and NB16 cell lines, which have an abundance of survivin, were more resistant to TRAIL\ and etoposide\induced cell death. 165 Survivin has also been found to cause the stabilization of the microtubules in the chromosomal passenger complex (CPC). 166 Various inhibitors have been found to target survivin in preclinical studies of NB. For example, YM155 decreases the survivin expression, inhibits the proliferation of and induces apoptosis in NB SH\SY5Y cells. 167 The same study has also shown that reduced expression of survivin after treatment with YM155 is effective to sensitize SH\SY5Y cells to cisplatin (chemotherapeutic agent), and induces tumor regression and apoptosis in SH\SY5Y xenograft model. 167 Rabbit polyclonal to Hsp90 Research conducted by Kunnimalaiyaan et al. 168 has demonstrated that LY2090314 (a GSK\3 inhibitor) is capable for causing growth inhibition and inducing apoptosis in NB cells, and also reducing the survivin level.?Withanolides (WA, WGA, WGB\DA, WGA\TA) have also been found to be cytotoxic to NB cells, potentially because they downregulate survivin in NB cells. 169 Noscapine, a nontoxic natural compound, induces apoptosis via downregulation of survivin in both p53 wild type and null NB cells. 170 Interestingly, the antidiabetic drug troglitazone also holds the capacity to sensitize NB cells to TRAIL\induced apoptosis via downregulation of survivin. 171 3.1.4. VEGF Tobramycin sulfate inhibitors VEGF is a 45?kDa dimeric Tobramycin sulfate glycoprotein that plays an important role in the formation of blood vessels (angiogenesis). 172 Apart from the functions of VEGF in angiogenesis and vascular permeability, the autocrine signaling of VEGF plays a role Tobramycin sulfate in cancer stem cells, and the Tobramycin sulfate resistance Tobramycin sulfate of tumor cells to treatments. 173 , 174 The human VEGF\A gene is positioned on chromosome 6 and contains eight exons. 175 Alternate splicing of the VEGF gene generates several isoforms, including VEGF121, VEGF189, and VEGF165, which are expressed in different human tumors. 176 , 177 Among the different isoforms of VEGF, VEGF165 mRNA is the predominant isoform expressed in.