Target For New Anticancer Interventions Research Articles

SurvivinT34A increases the therapeutic efficacy of arsenic trioxide in mouse hepatocellular carcinoma models.

Arsenic trioxide (ATO) has demonstrated clinical efficacy in acute promyelocytic leukemia (APL) and invitro activity in various solid tumors. As2O3 as single agent exhibits poor efficacy for treatment of hepatocellular carcinoma (HCC) in phase II trial, suggesting that new modalities of treatment with enhanced therapeutic effect and alleviated toxicity are needed for application of As2O3 on patients with HCC. Survivin is the strongest inhibitor of apoptosis protein over-expressed in tumors, which has been proposed as an attractive target for new anticancer interventions. Disruption of survivin by the plasmid encoding the phosphorylation-defective mouse survivin threonine 34→alanine mutant (Msurvivin T34A plasmid) has proved a promising strategy for suppressing a variety of murine cancer. In the present study, we attempted to test Msurvivin T34A and arsenic trioxide (ATO) on a cell line and mice bearing subcutaneous tumors, with regard to their effects and mechanisms. We observed that the co-treatment with surivinT34A and ATO significantly enhanced the antitumor activity by induction of apoptosis in Hepa1-6 tumor cells invitro, compared with control groups. The synergistic apoptosis-inducing effect of combination of these two drugs resulted in elevation of reactive oxygen species (ROS) level which could be antagonized by the antioxidant N-acetyl-l-cysteine. The combination treatment induced ROS-dependent collapse of the mitochondrial membrane potential. Moreover, the tumor growth invivo was also remarkably inhibited by combination of surivinT34A and ATO when compared with control groups. Our findings demonstrate that the combination of surivinT34A and ATO exerted synergistic antitumor effects, providing a new perspective for clinical treatment of HCC.

Delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA as a cancer therapeutic: a proof-of-concept study.

Survivin is a member of the inhibitor-of-apoptosis proteins family. It is overexpressed in many different cancer types but not in the differentiated normal tissue. In addition, overexpression of survivin promotes cancer cell survival and induces chemotherapeutic drug resistance, making it an attractive target for new anticancer interventions. Despite survivin being a promising molecular target for anticancer treatment, it is widely accepted that survivin is only a “semi-druggable” target. Therefore, it is important to develop a new strategy to target survivin for anticancer treatment. In this study, we constructed a novel survivin promoter-driven full-length antisense survivin (pSur/AS-Sur) expression plasmid DNA. Promoter activity assay revealed that the activity of the survivin promoter of pSur/AS-Sur correlated with the endogenous expression of survivin at the transcriptional level in the transfected A549, MDA-MB-231, and PANC-1 cancer cells. Western blot analysis showed that liposomal delivery of pSur/AS-Sur successfully downregulated the expression of survivin in A549, MBA-MB-231, and PANC-1 cells in vitro. In addition, delivery of pSur/AS-Sur induced autophagy, caspase-dependent apoptosis, and caspase-independent apoptosis as indicated by the increased LC3B-II conversion, autophagosome formation, caspase-9/-3 and poly(ADP-ribose) polymerase-1 cleavage, and apoptosis-inducing factor nuclear translocation in A549, MBA-MB-231, and PANC-1 cells. Importantly, liposomal delivery of pSur/AS-Sur was also capable of decreasing the proliferation of the survivin/MDR1 coexpressing multidrug-resistant KB-TAX50 cancer cells and the estrogen receptor-positive tamoxifen-resistant MCF7-TamC3 cancer cells in vitro. In conclusion, the results of this study suggest that delivery of a survivin promoter-driven antisense survivin-expressing plasmid DNA is a promising way to target survivin and to treat survivin-expressing cancers in the future.

Targeting 14-3-3zeta in cancer therapy

An effective therapeutic target is imperative for cancer treatment, including gene therapy. 14-3-3zeta, a member of the 14-3-3 protein family, acts as a suppressor of apoptosis and has a central role in tumor genesis and progression. Owing to its wide upregulation in human tumors and its involvement in cancer progression and treatment resistance, 14-3-3zeta is currently undergoing extensive investigation as a novel therapeutic target. In this review, we widely investigate the role of 14-3-3zeta in cancer and suggest a potential therapeutic target for new anticancer interventions.

Investigations of survivin: the past, present and future

Survivin is a member of the inhibitors-of-apoptosis protein (IAPs) family. It promotes cell survival through interference with multiple cell cycle-related proteins such as INCENP and Aurora B kinase. Survivin also inhibits cell death through interference with both caspase-dependent and -independent cell apoptosis. Interestingly, recent evidence suggests that survivin may also play a role in the regulation of cancer cell autophagy. At the clinical level, studies on clinical specimens have shown that survivin expression is up-regulated in various human cancers and its up-regulation is associated with tumour resistance to both chemotherapy and radiation therapy. On the basis of these findings, survivin has been proposed as an attractive target for new anti-cancer interventions. However, despite the role that survivin plays in cancer cell survival and anti-drug response, the development of survivin inhibitors is relatively slow as compared to other therapeutic inhibitors for cancer treatment. In this review, the relationships between survivin expression and the causation of drug resistance in cancers are re-addressed. This review also summarizes the recent development of survivin inhibitors for clinical usage.

Recent Advances in Anti-Survivin Treatments for Cancer

Apoptosis occurs via extrinsic or intrinsic signalling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis through survivin in tumour cells has been increasingly recognized as a promising approach for cancer therapy. Survivin has multiple functions including cytoprotection, inhibition of cell death, and cell-cycle regulation, especially at the mitotic process stage, all of which favour cancer survival. Many studies on clinical specimens have shown that survivin over expression is invariably up regulated in human cancers, associated with resistance to chemotherapy or radiation therapy, and linked to poor prognosis, suggesting that cancer cells survive with survivin. On the basis of these findings, survivin has been proposed as an attractive target for new anticancer interventions. Survivin inhibitors recently entered clinical trials. Recent studies suggest a possible role for survivin in regulating the function of normal adult cells. However, the expression and function of survivin in normal tissues are still not well characterized and understood. Still better understandings of survivin's role in tumour versus normal cells are needed for designing the strategies to selectively disrupt survivin in cancers. In the present review, we summarise the importance of recent survivin-targeted cancer therapy for future clinical application.

Report of the EORTC-PAMM Meeting, Brussels, March 16-18th, 2009

For the first time, the 2009 Pharmacology and Molecular Mechanisms (PAMM) winter meeting was organized in connection with the EGAM (EORTC Groups Annual Meeting) in Brussels. Furthermore, the PAMM participated in an additional plenary session together with the PathoBiology Group and the functional imaging group during the EGAM itself, in which the Laboratory Research Division summarized their expertise in translational research and gave an overview of what it can offer to the Disease Oriented Groups. The emphasis of the joint meeting was on novel concepts in cancer treatment and on new approaches to monitor therapy and implement personalized strategies. Three main subtopics could be possibly canvassed out of whole meeting, namely, (a) apoptosis and signalling, (b) cancer stem cells, (c) cancer genome and epigenome profiling. (a) Targeting apoptosis Most anti-cancer therapies act by triggering apoptosis in cancer cells. Therefore, defects in apoptosis programmes, for example aberrant expression of anti-apoptotic proteins, may render cancer cells resistant to treatment. Indeed, deregulation of apoptosis is one of the hallmarks of malignant cells, allowing their survival in the context of an altered genome and in harsh tumour environments with low levels of oxygen and nutrients. Understanding of the molecular mechanisms underlying apoptosis suppression in cancer has provided rationales for the design of apoptosis targeted therapies. One strategy was illustrated by Simone Fulda (University Children’s Hospital, Ulm, Germany) and involves the targeting of inhibitors of apoptosis proteins (IAPs), which are expressed at high levels in many human cancers and block apoptosis by inhibiting effector caspases. Fulda showed how targeting XIAP (one member of the IAP family) by RNA interference-mediated knockdown or small molecule inhibitors cooperates with TRAIL (tumour-necrosis-related apoptosis-induced ligand) to suppress growth in both in vitro and in vivo models of pancreatic cancer and in childhood acute leukaemia cells [14,25]. In this context, IAP inhibitors appear to be promising therapeutic tools, and they have recently entered early clinical trials in the form of small peptides. Nadia Zaffaroni (Fondazione IRCCS Istituto Nazionale dei tumouri, Milan, Italy) showed promising in vitro and in vivo data on ‘survivin’ inhibition, another member of the IAP family of apoptosis inhibitors. Survivin is a bifunctional protein that in addition to acting as a suppressor of programmed cell death also plays a central role in cell division. Owing to its massive up-regulation in human tumours and its involvement in cancer progression and treatment resistance, survivin is currently undergoing extensive investigation as a promising target for new anti-cancer interventions. Zaffaroni showed how the down-regulation of this protein, accomplished by means of various strategies (including the use of antisense oligonucleotides, small interfering RNAs, ribozymes, dominant negative mutants and small molecules antagonists) reduced tumour growth potential, increased the apoptotic rate and sensitized tumour cells to chemo- and radiotherapeutic agents in different tumour pre-clinical models [18]. The first survivin inhibitors have already reached the clinic: the YM155 molecule is currently in phase 1–2 studies [22]. However, due to its central role in promoting cell division in normal cells, the effects of survivin disruption on normal tissues and the related possible toxicities must be further investigated. Frank A Kruyt (University Medical Center Groningen, the Netherlands) presented his work on bortezomib, an interesting compound that can reversibly inhibit the proteasome and induce mitochondrial-dependent apoptosis [26]. Kruyt argued that bortezomib may be an interesting targeting moiety for non-small-cell lung cancer (NSCLC), a disease with poor survival rates, which represents 80–85% of lung cancer cases. The combined administration of TRAIL/bortezomib proved highly effective in inducing mitochondrial-dependent apoptosis in both in vitro and in vivo models of NSCLC. Mechanistic studies are ongoing to better understand the favourable drug interactions. In the clinic, recombinant TRAIL preparations and agonistic antibodies are under examination and combination strategies are in progress, including mapatumumab (TRAIL-R1/DR4 mAb) and bortezomib in multiple myeloma [6–8].

Efficient inhibition of murine breast cancer growth and metastasis by gene transferred mouse survivin Thr34-->Ala mutant.

BackgroundMetastasis in breast cancer is a vital concern in treatment because most women with primary breast cancer have micrometastases to distant sites at diagnosis. As a member of the inhibitor of apoptosis protein (IAP) family, survivin has been proposed as an attractive target for new anticancer interventions. In this study, we investigated the role of the plasmid encoding the phosphorylation-defective mouse survivin threonine 34→alanine mutant (Msurvivin T34A plasmid) in suppressing both murine primary breast carcinomas and pulmonary metastases.MethodsIn vitro study, induction of apoptosis by Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) was examined by PI staining fluorescence microscopy and flow cytometric analysis. The anti-tumor and anti-metastases activity of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) was evaluated in female BALB/c mice bearing 4T1 s.c. tumors. Mice were treated twice weekly with i.v. administration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol), PORF-9 null plasmid complexed with cationic liposome (DOTAP/Chol), 0.9% NaCl solution for 4 weeks. Tumor volume was observed. After sacrificed, tumor net weight was measured and Lung metastatic nodules of each group were counted. Assessment of apoptotic cells by TUNEL assay was conducted in tumor tissue. Microvessel density within tumor tissue was determined by CD31 immunohistochemistry. Alginate-encapsulated tumor cells test was conducted to evaluate the effect on angiogenesis. By experiment of cytotoxicity T lymphocytes, we test whether Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) can induce specific cell immune response.ResultsAdministration of Msurvivin T34A plasmid complexed with cationic liposome (DOTAP/Chol) resulted in significant inhibition in the growth and metastases of 4T1 tumor model. These anti-tumor and anti-metastases responses were associated with triggering the apoptosis of tumor cells directly, inhibiting angiogenesis and inducing specific cellular immune response.ConclusionThe present findings suggest that the Msurvivin T34A plasmid complexed with cationic liposome may provide an effective approach to inhibit the growth and metastases of a highly metastatic mouse breast cancer model with minimal side effects.

Targeting survivin in cancer therapy

Background: Survivin is a structurally unique member of the inhibitor of apoptosis protein (IAP) family that acts as a suppressor of apoptosis and plays a central role in cell division. Owing to its massive upregulation in human tumors and its involvement in cancer progression and treatment resistance, survivin is currently undergoing extensive investigation as a novel therapeutic target. Objective: The purpose of this review is to define the potential of survivin as a therapeutic target for new anticancer interventions. Methods: The literature dealing with the therapeutic targeting of survivin has been carefully reviewed. Results/conclusion: Several preclinical studies have demonstrated that downregulation of survivin expression or function, accomplished by means of various strategies, reduced tumor growth potential, increased the apoptotic rate and sensitized tumor cells to chemotherapeutic drugs and radiation in different human tumor models. Moreover, the first survivin inhibitors are being currently evaluated in clinical settings.

Targeting survivin in cancer therapy: fulfilled promises and open questions

Survivin is a bifunctional protein that acts as a suppressor of apoptosis and plays a central role in cell division. The protein is strongly expressed in the most common human neoplasms, has prognostic relevance for some of them and appears to be involved in tumor cell resistance to anticancer agents and ionizing radiation. On the basis of these findings, survivin has been proposed as an attractive target for new anticancer interventions. Several preclinical studies have demonstrated that down-regulation of survivin expression or function, accomplished by means of various strategies, reduced tumor growth potential, increased the apoptotic rate and sensitized tumor cells to chemotherapeutic drugs and radiation in different human tumor models. Moreover, the first survivin inhibitors recently entered clinical trials. Recent studies suggest a possible role for survivin in regulating the function of normal adult cells. However, the expression and function of survivin in normal tissues are still not well characterized and understood. Better knowledge of the role of survivin in tumor versus normal cells will be instrumental for the design of optimal strategies to selectively disrupt survivin in cancer.

Survivin as a target for new anticancer interventions

Survivin is a member of the inhibitor of apoptosis protein (IAP) family, that has been implicated in both control of cell division and inhibition of apoptosis. Specifically, its anti-apoptotic function seems to be related to the ability to directly or indirectly inhibit caspases. Survivin is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to some anticancer agents and ionizing radiation. On the basis of these findings survivin has been proposed as an attractive target for new anticancer interventions. Several preclinical studies have demonstrated that down-regulation of survivin expression/function, accomplished through the use of antisense oligonucleotides, dominant negative mutants, ribozymes, small interfering RNAs and cyclin-dependent kinase inhibitors, increased the apoptotic rate, reduced tumor-growth potential and sensitized tumor cells to chemotherapeutic drugs with different action mechanisms and gamma-irradiation in in vitro and in vivo models of different human tumor types.

Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions.

Survivin is a structurally unique member of the inhibitors of apoptosis protein (IAP) family that is involved in both control of cell division and inhibition of apoptosis. Its anti-apoptotic function seems to be related to its ability to directly or indirectly inhibit caspases, although the precise role of survivin in the modulation of the caspase cascade has not been fully elucidated. Survivin has been described to be selectively expressed in the most common human neoplasms and to be associated with clinical tumour progression. Moreover, the protein appears to be involved in tumour cell resistance to some anticancer agents and ionizing radiation. On the basis of these findings survivin has been proposed as a promising target for new anticancer interventions. In in vitro and in vivo studies targeting survivin with antisense oligonucleotides, dominant negative mutants or ribozymes have shown to induce apoptosis, reduce tumour-growth potential and sensitise tumour cells to chemotherapeutic drugs such as Taxol, cisplatin and etoposide, gamma-irradiation, and immunotherapy.