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The Heat Shock Response: Its Role in Pathogenesis of Type 2 Diabetes and Its Complications, and Implications for Therapeutic Intervention

Abstract: The heat shock response (HSR) is an evolutionarily conserved mechanism that cells and organisms utilize to protect themselves from the damaging effects of stress. Induction of HSR involves a complex multi-step process in which heat shock factor-1 (HSF-1), the key modulator of HSR, is activated, leading to the induction of a variety of heat shock genes. There is evidence that the HSR is defective in diabetes, which makes the tissues vulnerable to stress-induced pathological changes. Consistent with this observation, induction of HSR by either non-pharmacological methods such as hyperthermia or by pharmacological inducers has beneficial effects in managing insulin resistance and hyperglycemia, as well as secondary complications of diabetes, such as cardiovascular disease, nephropathy, neuropathy, and retinopathy as well as wound healing. This review summarizes what is currently known about the role of the HSR in diabetes and therapeutic implications of enhancing HSR in the management of diabetes and its associated complications, focusing on small molecule mediated therapeutics. ... Read more

Tumor Heterogeneity, Clonal Evolution, and Therapy Resistance: An Opportunity for Multitargeting Therapy

Abstract: Heterogeneity within the cell population is a feature of many tumors. This lack of cellular homogeneity may originate from a number of sources, including differential nutrient status due to the de novo microcirculations of tumors, to infiltration of normal cells into the tumor, and to the hierarchical natures of the cell populations from which cancers arise. Tumors are thought to arise from one or more tumor initiating cells (TIC) within the population and to found hierarchies of progenitors and more differentiated cancer cells. TIC are often derived from tissue stem cells and these cancer stem cells are characterized by resistance to most cytotoxic treatments and by a high metastatic rate. Many of the properties of tumor populations, including the ability to express mutated oncogenes and to evolve new features such as treatment resistance and invasive and metastatic potential appear to depend on the molecular chaperone Hsp90. We discuss the potential of targeting the heterogeneous cell population with Hsp90 inhibitory drugs and its potential ability to inactivate TIC and to block the evolution of new phenotypes in cancer. ... Read more

The Role of Telomeres and Telomerase in Endocrine Tumors

Abstract: The enzyme, telomerase, is a reverse transcriptase that synthesizes the telomeric ends of linear chromosomes and compensate for the shortened telomere, thereby immortalizing the cell. It is present at the blastocyst stage of embryological development, low or undetectable in most somatic cells, and activated in cancer. Because of its strong association with cancer cell immortalization and proliferation, numerous attempts have been made to capitalize on its diagnostic, prognostic, and therapeutic potential. Herein we discuss the role of telomerase in normal, benign, and cancerous endocrine tissues. ... Read more

Hsp90 Inhibitors as Selective Anticancer Drugs

Abstract: Heat shock protein 90 (Hsp90) proves to be one of the few cancer drug targets that are cancer-specific and are less likely to induce drug resistance over time. Though universally present, Hsp90 assumes a special shape in cancer cells and hence becomes a unique target. Because of its critical role in cell survival, it does not often mutate and therefore it is not prone to drug resistance. ... Read more

Heat Shock Protein Active in Cancer Cells, Offers Target for Cancer Drugs

Researchers discovered that Heat Shock Protein 90 (Hsp90) could be a cancer specific therapeutic target. Hsp90 is a chaperone protein that shepherds the maturation of oncogenic proteins such as HER-2, Bcr-Abl, mutated p53, and others.

Adeela Kamal and colleagues from Conforma Therapeutics Corp., San Diego, CA have found that inhibitors for Hsp90 have knocked the Hsp90 into disarray and left them unable to “serve their clients.” Although Hsp90 is abundant in the majority of cells, including cancer cells, inhibitors of Hsp90 selectively kill cancer cells. Authors showed that Hsp90 in cancer cells bind to an Hsp90 inhibitor called 17-allylaminogeldanamycin (17-AAG) with ... Read more

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