Studies on survivin over the past 2-3 years have shown that survivin possesses multiple subcellular localizations and is a multi-functional molecule involved in many aspects of cellular processes and/ or behaviors. The subcellular localization and function of the survivin splice variants, however, have not yet been well elucidated. We have, therefore, provided additional observations on several survivin splice variants for further exploration. This review article will update the role of survivin, and its splice variants in the mitosis/cell cycle, apoptosis, tumorigenesis, chemoprevention, drug/radiation resistance, and cancer therapeutics.Recent studies have indicated that the survivin molecule is not only localized on the mitotic apparatus and the centromere/kinetochore of chromosomes, but it is also localized on mitochondria. The multi-subcellular localization of survivin is consistent with its multiple functions in cellular metabolisms and responses. Alternative splicing of the survivin gene transcript produces a number of different survivin splice variant mRNAs (Fig. 1A), which encode different proteins (Fig. 1B). These survivin splice variants/isoforms appear to have unique subcellular localizations and functions as well. Moreover, new and yet to be characterized survivin splice variants have been found from EST databases (Fig. 2). The presence of these survivin splice variants may make the survivin gene even more functionally diverse and more strictly regulated. In the present review, we will update the role of survivin and its splice variants in the mitosis/cell cycle, apoptosis, tumorigenesis, chemoprevention, drug/radiation resistance, and cancer therapeutics. ROLE OF SURVIVIN IN THE CONTROL OF MITOSIS AND CELL CYCLEAlthough the precise mechanism remains to be elucidated, survivin exerts a role in cell division control by its association with Aurora B and INCENP on the centromere/kinetochore to form a chromosome passage protein complex (Li, 2003). A significant progression has been made in this area since then. Honda et al. (2003) reported that RNAi depletion of either Aurora B, INCENP, or survivin impaired the localization of the entire Aurora B/INCENP/survivin complex to centromeres and the central spindle, and severely disturbed mitotic progression. Using recombinant proteins, however, it has been shown that INCENP, but not survivin, stimulated Aurora B kinase activity in vitro (Honda et al., 2003). This finding disagrees with an earlier finding that the presence of survivin enhances Aurora B kinase activity in vitro [see review (Li, 2003)]. Nevertheless, Wheatley et al. (2004) found that survivin is specifically phosphorylated in vitro by Aurora-B kinase at the Thr117 site, and that a survivin-T117A mutant prevents the in vitro survivin phosphorylation by Aurora B. Interestingly, while the *Correspondence to: Fengzhi Li, PhD, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and, Carlton Streets, Buffalo, New York., fengzhi.li@roswellpark.org. survivin-T117A mut...

Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 µM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118’s effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials.

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.

Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers, for example, in ~36% of hepatocellular carcinomas (HCCs) and ~68% of non–small cell lung cancers (NSCLCs). Current methods for restoration of p53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, a redox-responsive nanoparticle (NP) platform is engineered for effective delivery of p53-encoding synthetic messenger RNA (mRNA). We demonstrate that the synthetic p53-mRNA NPs markedly delay the growth of p53-null HCC and NSCLC cells by inducing cell cycle arrest and apoptosis. We also reveal that p53 restoration markedly improves the sensitivity of these tumor cells to everolimus, a mammalian target of rapamycin (mTOR) inhibitor that failed to show clinical benefits in advanced HCC and NSCLC. Moreover, cotargeting of tumor-suppressing p53 and tumorigenic mTOR signaling pathways results in marked antitumor effects in vitro and in multiple animal models of HCC and NSCLC. Our findings indicate that restoration of tumor suppressors by the synthetic mRNA NP delivery strategy could be combined together with other therapies for potent combinatorial cancer treatment.

Survivin is a novel anti-apoptotic protein that is highly expressed in cancer but is undetectable in most normal adult tissues. It was reported that taxol-mediated mitotic arrest of cancer cells is associated with survivin induction, which preserves a survival pathway and results in resistance to taxol. In this study, we provide new evidence that induction of survivin by taxol is an early event and is independent of taxol-mediated G 2 /M arrest. Taxol

Despite the broad antitumor spectrum of cisplatin, its therapeutic efficacy in cancer treatment is compromised by the development of drug resistance in tumor cells and systemic side effects. A close correlation has been drawn between cisplatin resistance in tumor cells and increased levels of intracellular thiol-containing species, especially glutathione (GSH). The construction of a unique nanoparticle (NP) platform composed of poly(disulfide amide) polymers with a high disulfide density for the effective delivery of Pt(IV) prodrugs capable of reversing cisplatin resistance through the disulfide-group-based GSH-scavenging process, as described herein, is a promising route by which to overcome limitations associated with tumor resistance. Following systematic screening, the optimized NPs (referred to as CP5 NPs) showed a small particle size (76.2 nm), high loading of Pt(IV) prodrugs (15.50% Pt), a sharp response to GSH, the rapid release of platinum (Pt) ions, and notable apoptosis of cisplatin-resistant A2780cis cells. CP5 NPs also exhibited long blood circulation and high tumor accumulation after intravenous injection. Moreover, in vivo efficacy and safety results showed that CP5 NPs effectively inhibited the growth of cisplatin-resistant xenograft tumors with an inhibition rate of 83.32% while alleviating serious side effects associated with cisplatin. The GSH-scavenging nanoplatform is therefore a promising route by which to enhance the therapeutic index of Pt drugs used currently in cancer treatment.

Spurred by recent progress in medicinal chemistry, numerous lead compounds have sprung up in the past few years, although the majority are hindered by hydrophobicity, which greatly challenges druggability. In an effort to assess the potential of platinum (Pt) candidates, the nanosizing approach to alter the pharmacology of hydrophobic Pt(IV) prodrugs in discovery and development settings is described. The construction of a self-assembled nanoparticle (NP) platform, composed of amphiphilic lipid-polyethylene glycol (PEG) for effective delivery of Pt(IV) prodrugs capable of resisting thiol-mediated detoxification through a glutathione (GSH)-exhausting effect, offers a *

Developing economical and efficient electrocatalysts with nonprecious metals for the hydrogen evolution reaction (HER), especially in water-alkaline electrolyzers, is pivotal for large-scale hydrogen production. Recently, both density functional theory (DFT) calculations and experimental studies have demonstrated that earth-abundant MoS 2 is a promising HER electrocatalyst in acidic solution. However, the HER kinetics of MoS 2 in alkaline solution still suffer from a high overpotential (90−220 mV at a current density of 10 mA cm −2 ). Herein, we report a combined experimental and first-principle approach toward achieving an economical and ultraefficient MoS 2 -based electrocatalyst for the HER by fine-tuning the electronic structure of MoS 2 nanorods with N and Mn dopants. The developed N,Mn codoped MoS 2 catalyst exhibits an outstanding HER performance with overpotentials of 66 and 70 mV at 10 mA cm −2 in alkaline and phosphate-buffered saline media, respectively, and corresponding Tafel slopes of 50 and 65 mV dec −1 . Moreover, the catalyst also exhibits long-term stability in HER tests. DFT calculations suggest that (1) the electrocatalytic performance can be attributed to the enhanced conductivity and optimized electronic structures for facilitating H* adsorption and desorption after N and Mn codoping and (2) N and Mn dopants can greatly activate the catalytic HER activity of the Sedge for MoS 2 . The discovery of a simple approach toward the synthesis of highly active and low-cost MoS 2 -based electrocatalysts in both alkaline and neutral electrolytes allows the premise of scalable production of hydrogen fuels.