shepherdin and Neoplasms

A crucial process in biology is the conversion of the genetic information into functional proteins that carry out the genetic program. However, a supplementary step is required to obtain functional proteins: the folding of the newly translated polypeptides into well-defined, three-dimensional conformations. Proteins chaperones are crucial for this final step in the readout of genetic information, which results in the formation of functional proteins. In this review, a special attention will be given to the strategies targeting hsp90 family members in order to increase cancer cell death. We argue that disruption of hsp90 machinery and the further client protein degradation is the main consequence of hsp90 oxidative cleavage taking place at the N-terminal nucleotide-binding site. Moreover, modulation of Grp94 expression will be discussed as a potential therapeutic goal looking for a decrease in cancer relapses.

Topics: Animals; Antineoplastic Agents; Cell Death; Drug Delivery Systems; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Oxidative Stress; Pentacyclic Triterpenes; Peptide Fragments; Triterpenes

Research has shown that cancer cells exhibit multiple deregulated pathways, involving proliferation, migration and cell death. Heat-shock-proteins have evolved as "central regulators" and are implicated in the modulation of these pathways and in organelle-specific signaling. In this instance, heat-shock-proteins (Hsps) assist cancer cells in the maturation of proteins. Hsp90 is of particular interest because its enzymatic ATPase activity is elevated in malignant cells as compared to non-neoplastic counterparts. Consistent with its high-activity in cancer cells, Hsp90 stabilizes a considerable number of proteins being instrumental in carcinogenesis and the maintenance and growth of highly malignant cancers. Among its distribution Hsp90 is also localized within mitochondria of neoplastic cells of various origin, interacting with another chaperone, TRAP1 (Tumor necrosis factor type 1 receptor-associated protein or Heat-shock-protein 75) to antagonize the cell death promoting properties of the matrix protein, Cyclophilin-D. Several preclinical studies, including in vivo studies in both orthotopic and genetic animal models, have confirmed that targeting mitochondrial Hsp90 may be a novel efficient treatment method for highly recalcitrant tumors. This review summarizes the most recent findings of mitochondrial Hsp90 signaling and its potential implications for cancer therapy.

Topics: Aminoimidazole Carboxamide; Animals; Antineoplastic Agents; Autophagy; Benzoquinones; Cyclophilins; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mitochondria; Molecular Chaperones; Molecular Targeted Therapy; Neoplasms; Peptide Fragments; Ribonucleotides; Signal Transduction; TOR Serine-Threonine Kinases

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.

Topics: Apoptosis; Cysteine Proteinase Inhibitors; Genetic Therapy; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasms; Peptide Fragments; Survivin

Tat peptides are useful carriers for delivering biologic molecules into the cell for both functional analysis of intracellular disease-related proteins and treatment of refractory diseases. Most internalized Tat-fused cargos (Tat-cargos) are trapped within the endosome, however, which limits the biologic function of the cargo. In this study, we demonstrated that Tat-fused HA2 peptide (HA2Tat), an endosome disrupted peptide, enhanced the endosome-escape efficiency of Tat-cargos. In cells treated with a mixture of fluorescein isothiocyanate-labeled Tat and HA2Tat, widespread fluorescence was observed throughout the cytosol. In addition, this HA2Tat-mediated cytosolic delivery technique led to enhanced cytotoxicity of Tat-fused anti-cancer peptides, specifically shepherdin. Thus, we improved the function of the delivered molecules by co-treating with HA2Tat and propose that this is a useful method for the delivery of therapeutic macromolecules into the cytosol.

Topics: Cell Line, Tumor; Cell Survival; Cytosol; Endosomes; Fluorescein-5-isothiocyanate; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Peptide Fragments; Peptides; Protein Transport; tat Gene Products, Human Immunodeficiency Virus

Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability. Here we present a combined structure- and dynamics-based computational design strategy, taking the flexibility of the receptor and of a lead peptidic antagonist into account explicitly, to identify the nonpeptidic small molecule 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) as a structurally novel inhibitor of Hsp90. The compound is selected to bind the Hsp90 N-terminal domain, mimicking the chemical and conformational properties of the recently described peptidic antagonist of the survivin-Hsp90 complex, shepherdin [Plescia et al. Cancer Cell 2005, 7, 457-468]. Experimental tests show that AICAR binds the Hsp90 N-domain, destabilizes multiple Hsp90 client proteins in vivo, including survivin, and exhibits antiproliferative and proapoptotic activity in multiple tumor cell lines, while not affecting proliferation of normal human fibroblasts. We propose that AICAR represents a viable lead for further development of anticancer drugs with wide therapeutic opportunities.

Topics: Aminoimidazole Carboxamide; Antineoplastic Agents; Apoptosis; Cell Proliferation; Combinatorial Chemistry Techniques; Computer Simulation; Drug Design; HSP90 Heat-Shock Proteins; Humans; Hypoglycemic Agents; Models, Molecular; Neoplasms; Peptide Fragments; Recombinant Proteins; Ribonucleotides; Tumor Cells, Cultured