knk-437 and Neoplasms

Described is the role that heat shock factor 1 (HSF1) plays in regulating cellular stress. Focusing on the current state of the HSF1 field in chemotherapeutics we outline the cytoprotective role of HSF1 in the cell. Summarizing the mechanism by which HSF1 regulates the unfolded proteins that are generated under stress conditions provides the background on why HSF1, the master regulator, is such an important protein in cancer cell growth. Summarizing siRNA knockdown results and current inhibitors provides a comprehensive evaluation on HSF1 and its current state. One set of molecules stands out, in that they completely obliterate the levels of HSF1, while simultaneously inhibiting heat shock protein 90 (Hsp90). These molecules are extremely promising as chemotherapeutic agents and as tools that may ultimately provide the connection between Hsp90 inhibition and HSF1 protein levels.

Topics: HSP90 Heat-Shock Proteins; Humans; Neoplasms; Transcription Factors

The anticancer effects of histone deacetylase inhibitors (HDACi) vary between patients, and their molecular mechanisms remain poorly understood. Previously, we have identified heat shock 70 kDa protein 1A (HSPA1A, also known as HSP72) as the most overexpressed protein in valproic acid (VPA)-resistant cell lines. KNK437, an inhibitor of heat shock proteins, enhanced the cytotoxic effects of not only VPA but also vorinostat, another HDACi. However, the mechanisms underlying the role of HSP72 in resistance against HDACi remain largely unknown.. The purpose of this study was to identify the mechanisms underlying the role of HSP72 in HDACi resistance.. We established an HSP72-overexpressing Jurkat cell line and used it to assess the functional role of HSP72 following treatment with the HDACi vorinostat and VPA.. HDACi-induced apoptosis, assessed using annexin V assays, sub-G1 fraction analysis, and PARP cleavage, was significantly lower in HSP72-overexpressing cells than in control cells. The HDACi-induced upregulation in caspase-3, -8, and -9 activity, as well as the HDACi-induced reduction in mitochondrial membrane potential, were also suppressed following HSP72 overexpression. The basal expression levels of Bcl-2, phosphorylated Bad, and XIAP increased in HSP72-overexpressing cells, whereas HDACi-induced Bid truncation and the suppression of Bad expression. Furthermore, vorinostat-induced histone hyperacetylation was also diminished in HSP72-overexpressing cells.. These findings clearly demonstrate that HSP72 inhibits HDACi-induced apoptosis.

Topics: Acetylation; Apoptosis; Benzhydryl Compounds; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; HSP70 Heat-Shock Proteins; HSP72 Heat-Shock Proteins; Humans; Hydroxamic Acids; Jurkat Cells; Neoplasms; Pyrrolidinones; Up-Regulation; Valproic Acid; Vorinostat

KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1α. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1α in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1α levels in KNK437-treated cells. This suggested that the absence of HIF-1α in hypoxic cells was not due to the enhanced protein degradation. HIF-1α is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1α mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1α levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways.

Topics: Benzhydryl Compounds; Cell Hypoxia; Cell Line, Tumor; Cell Survival; DNA-Binding Proteins; Heat Shock Transcription Factors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Proto-Oncogene Proteins c-akt; Pyrrolidinones; Radiation Tolerance; Radiation-Sensitizing Agents; Stress, Physiological; Transcription Factors