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Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells  [cached]
Horibe Tomohisa,Torisawa Aya,Kohno Masayuki,Kawakami Koji
Molecular Cancer , 2012, DOI: 10.1186/1476-4598-11-59
Abstract: Background Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo. Results In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition. Conclusion These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
Ligand Recognition by the TPR Domain of the Import Factor Toc64 from Arabidopsis thaliana  [PDF]
Rashmi Panigrahi, Abdussalam Adina-Zada, James Whelan, Alice Vrielink
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083461
Abstract: The specific targeting of protein to organelles is achieved by targeting signals being recognised by their cognate receptors. Cytosolic chaperones, bound to precursor proteins, are recognized by specific receptors of the import machinery enabling transport into the specific organelle. The aim of this study was to gain greater insight into the mode of recognition of the C-termini of Hsp70 and Hsp90 chaperones by the Tetratricopeptide Repeat (TPR) domain of the chloroplast import receptor Toc64 from Arabidopsis thaliana (At). The monomeric TPR domain binds with 1:1 stoichiometry in similar micromolar affinity to both Hsp70 and Hsp90 as determined by isothermal titration calorimetry (ITC). Mutations of the terminal EEVD motif caused a profound decrease in affinity. Additionally, this study considered the contributions of residues upstream as alanine scanning experiments of these residues showed reduced binding affinity. Molecular dynamics simulations of the TPR domain helices upon peptide binding predicted that two helices within the TPR domain move backwards, exposing the cradle surface for interaction with the peptide. Our findings from ITC and molecular dynamics studies suggest that AtToc64_TPR does not discriminate between C-termini peptides of Hsp70 and Hsp90.
Intracellular Distribution-based Anticancer Drug Targeting: Exploiting a Lysosomal Acidification Defect Associated with Cancer Cells  [cached]
Rosemary A. Ndolo,Damon T. Jacobs,M. Laird Forrest,Jeffrey P. Krise
Molecular and Cellular Pharmacology , 2010,
Abstract: The therapeutic usefulness of anticancer agents relies on their ability to exert maximal toxicity to cancer cells and minimal toxicity to normal cells. The difference between these two parameters defines the therapeutic index of the agent. Towards this end, much research has focused on the design of anticancer agents that have optimized potency against a variety of cancer cell types; however, much less effort is spent on the design of drugs that are minimally toxic to normal cells. We have previously described a concept for a novel drug delivery platform that relies on the propensity of drugs with optimal physicochemical properties to distribute differently in normal versus cancer cells due to differences in intracellular pH gradients. Specifically, we demonstrated in vitro that certain weakly basic anticancer agents had the propensity to distribute to intracellular locations in normal cells that prevent interaction with the drug target, and to intracellular locations in cancer cells that promote drug-target interactions. We refer to this concept broadly as intracellular distribution-based drug targeting. Here we will discuss current in vivo work from our laboratory that examined the role of lysosome pH on the intracellular distribution and toxicity of inhibitors of the Hsp90 molecular chaperone in mice.
Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy  [PDF]
Han-Chung Wu,De-Kuan Chang
Journal of Oncology , 2010, DOI: 10.1155/2010/723798
Abstract: Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy. 1. Introduction One of the primary goals of a successful cancer treatment regimen is to deliver sufficient amounts of drug to tumors while minimizing damage to normal tissues. Most chemotherapeutic agents enter normal tissues in the body with indiscriminate cytotoxicity and do not preferentially accumulate at tumor sites. At times the dose reaching the tumor may be as little as 5% to 10% of the doses accumulating in normal organs [1, 2]. One reason for the inability for drugs to accumulate at target sites is that the interstitial fluid pressure (IFP) in solid tumors is higher than in normal tissues, that blocking transcapillary transport of chemotherapeutic drugs or antibodies [3–5]. In this way, the anticancer effect is decreased and toxic effect to normal cells is increased. Fear of severely harming the patients often limits the dose of anticancer drugs that can be given to a patient. These lower than optimal doses elicit incomplete tumor responses which leads to disease relapse and drug resistance. Therefore, most cancer drugs fail in clinical studies not because they are ineffective in killing cancer cells but because they cannot be administered in doses high enough to eradicate the tumor without severely harming the patient. Several approaches have been developed to improve the ability of anticancer drug to more specifically target tumors and avoid normal organs. One of the most effective strategies is to encapsulate drugs in particles that deliver them preferentially to tumor sites. For example, liposome particles have been found able
Photodynamic Therapy with Hypericin Improved by Targeting HSP90 Associated Proteins  [PDF]
Peter Solár,Mária Chytilová,Zuzana Solárová,Ján Moj?i?,Peter Ferenc,Peter Fedoro?ko
Pharmaceuticals , 2011, DOI: 10.3390/ph4111488
Abstract: In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic activity, viability and cell number when combined with photodynamic therapy with hypericin. Moreover, IC 10 concentation of 17-DMAG resulted in significant increase of SKBR-3 cells in G1 phase of the cell cycle, followed by an increase of cells in G2 phase when combined with photodynamic therapy. Furthermore, 17-DMAG already decreased HER2, Akt, P-Erk1/2 and survivin protein levels in SKBR-3 cells a short time after its application. In this regard, 17-DMAG protected also SKBR-3 cells against both P-Erk1/2 as well as survivin upregulations induced by photodynamic therapy with hypericin. Interestingly, IC 10 concentration of 17-DMAG led to total depletion of Akt, P-Erk1/2 proteins and to decrease of survivin level at 48 h. On the other hand, 17-DMAG did not change HER2 relative expression in SKBR-3 cells, but caused a significant decrease of HER2 mRNA in MCF-7 cells characterized by low HER2 expression. These results show that targeting HSP90 client proteins increases the efficiency of antineoplastic effect of photodynamic therapy in vitro.
The Human TPR Protein TTC4 Is a Putative Hsp90 Co-Chaperone Which Interacts with CDC6 and Shows Alterations in Transformed Cells  [PDF]
Gilles Crevel, Dorothy Bennett, Sue Cotterill
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001737
Abstract: Background The human TTC4 protein is a TPR (tetratricopeptide repeat) motif-containing protein. The gene was originally identified as being localized in a genomic region linked to breast cancer and subsequent studies on melanoma cell lines revealed point mutations in the TTC4 protein that may be associated with the progression of malignant melanoma. Methodology/Principle Findings Here we show that TTC4 is a nucleoplasmic protein which interacts with HSP90 and HSP70, and also with the replication protein CDC6. It has significant structural and functional similarities with a previously characterised Drosophila protein Dpit47. We show that TTC4 protein levels are raised in malignant melanoma cell lines compared to melanocytes. We also see increased TTC4 expression in a variety of tumour lines derived from other tissues. In addition we show that TTC4 proteins bearing some of the mutations previously identified from patient samples lose their interaction with the CDC6 protein. Conclusions/Significance Based on these results and our previous work with the Drosophila Dpit47 protein we suggest that TTC4 is an HSP90 co-chaperone protein which forms a link between HSP90 chaperone activity and DNA replication. We further suggest that the loss of the interaction with CDC6 or with additional client proteins could provide one route through which TTC4 could influence malignant development of cells.
Advances in Targeting HER3 as an Anticancer Therapy  [PDF]
Ning Jiang,Nabil F. Saba,Zhuo Georgia Chen
Chemotherapy Research and Practice , 2012, DOI: 10.1155/2012/817304
Abstract: HER3 (ErbB3) is a unique member of the human epidermal growth factor receptor (EGFR) family (ErbB family). It functions only through dimerization with other members of the ErbB family and modulates activity and sensitivity to targeted cancer therapies. This paper briefly describes the mechanism of HER3 in signal transduction and its potential role in acquired resistance to EGFR- and HER2-targeted therapies. We also consider recent developments in HER3-targeting therapeutics and their combination with inhibitors of other ErbB members in clinical applications.
Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance  [PDF]
Dea Shahinas,Asongna Folefoc,Dylan R. Pillai
Pathogens , 2013, DOI: 10.3390/pathogens2010033
Abstract: Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.
Alemu Tekewe*, Murad Saleh and Meron Kassaye
International Journal of Pharmaceutical Sciences and Research , 2013,
Abstract: The treatment of cancer is limited by a number of factors including the low therapeutic index of most chemotherapeutic agents, the emergence of drug- and radiation-resistant tumor cells, tumor heterogeneity and the presence of metastatic disease. One of the means to improve the therapeutic index of drugs is by selective or ‘targeted’ delivery to tumor sites. Tumor-directed therapy has the potential to improve efficacy, by increasing the intratumoral concentration of the targeted agent, and to minimize toxicity by reducing systemic exposure. So far some degree of site-selective delivery has been achieved only with “targeting homing drugs” that specifically recognize their pharmacological target. The specificity of delivery using nanoparticles was initially a coincidental property, active targeting has now become a central concept in cancer therapeutic research. This concept has been developed into practical application using a variety of tumor targeting ligands. This review briefly summarizes the ever increasing evidence to the use of proteins such as monoclonal antibodies (MAbs), bispecific antibodies (BsAbs), Affibody molecules, albumin, transferrin and peptides such as stable microbial toxins and cell penetrating peptides (CPPs) as innovative tumor targeting ligands in anticancer drug delivery systems.
Advances in Targeting HER3 as an Anticancer Therapy  [PDF]
Ning Jiang,Nabil F. Saba,Zhuo Georgia Chen
Chemotherapy Research and Practice , 2012, DOI: 10.1155/2012/817304
Abstract: HER3 (ErbB3) is a unique member of the human epidermal growth factor receptor (EGFR) family (ErbB family). It functions only through dimerization with other members of the ErbB family and modulates activity and sensitivity to targeted cancer therapies. This paper briefly describes the mechanism of HER3 in signal transduction and its potential role in acquired resistance to EGFR- and HER2-targeted therapies. We also consider recent developments in HER3-targeting therapeutics and their combination with inhibitors of other ErbB members in clinical applications. 1. Introduction HER3 is one member of the human epidermal growth factor receptor (EGFR) family which consists of four types of transmembrane tyrosine kinase receptors, HER1 (EGFR, ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4) (Figure 1). The general structure of ErbB members includes an extracellular ligand-binding region, an -helical transmembrane segment, a cytoplasmic tyrosine-kinase-containing domain, and a C-terminal phosphorylation tail [1, 2]. ErbB members are widely expressed in epithelial, mesenchymal, and neuronal tissues and regulate cell division, proliferation, differentiation, and other normal cellular processes [3, 4]. These membrane receptors receive extracellular signals from their ligands including those preferentially binding to EGFR such as epidermal growth factor (EGF), epiregulin, betacellulin, transforming growth factor- (TGF- ), as well as neuregulins which only bind to HER3 and HER4 [5, 6]. Their normal physiological expression and function are controlled by the spatial and temporal expression of these ligands. Ligand binding triggers intracellular signaling through the formation of heterodimers or homodimers between ErbB receptors. Two key signaling pathways activated by the ErbB family are the RAS/RAF/MAPK pathway, which stimulates proliferation, and the PI3?K/Akt pathway, which promotes tumor cell survival [7]. As a result, the recruitment of intracellular signaling molecules and activation of a tightly controlled array of signaling pathways drive and regulate cell proliferation, and organ development and repair [1, 6]. Figure 1: General features of the HER family. EGFR, HER3, HER4 have intact ligand binding sites. HER2 fails to bind any known ErbB ligands and HER3 has impaired catalytic activity. Two main strategies to target HER receptors for cancer treatment include monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI) approaches. The HER2-HER3 heterodimer is considered the most potent HER pair as an oncogenic unit and is illustrated as a
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