stilbenes and tanespimycin

Topics: Antineoplastic Agents; Benzamides; Benzoquinones; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dioxoles; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imatinib Mesylate; Isoquinolines; Lactams, Macrocyclic; Neoplasms; Piperazines; Pyrazines; Pyrimidines; Rifabutin; Stilbenes; Tetrahydrofolates; Tetrahydroisoquinolines; Trabectedin; Vorinostat

Heat shock protein 90 (HSP90) is an exciting new target in cancer therapy. Repair protein Rad51 is involved in protecting non-small cell lung cancer (NSCLC) cell lines against chemotherapeutic agent-induced cytotoxicity. This study investigated the role of Rad51 expression in HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-induced cytotoxicity in two NSCLC cell lines, A549 and H1975. The 17-AAG treatment decreased cellular Rad51 protein and mRNA levels and phosphorylated MKK1/2-ERK1/2 protein levels, and disrupted the HSP90 and Rad51 interaction. This triggered Rad51 protein degradation through the 26S proteasome pathway. The 17-AAG treatment also decreased the NSCLC cells' DNA repair capacity, which was restored by the forced expression of the Flag-Rad51 vector. Specific inhibition of Rad51 expression by siRNA further enhanced 17-AAG-induced cytotoxicity. In contrast, enhanced ERK1/2 activation by the constitutively active MKK1/2 (MKK1/2-CA) vector significantly restored the 17-AAG-reduced Rad51 protein levels and cell viability. Arachidin-1, an antioxidant stilbenoid, further decreased Rad51 expression and augmented the cytotoxic effect and growth inhibition of 17-AAG. The 17-AAG and arachidin-1-induced synergistic cytotoxic effects and decreased DNA repair capacity were abrogated in lung cancer cells with MKK1/2-CA or Flag-Rad51 expression vector transfection. In conclusion, HSP90 inhibition induces cytotoxicity by down-regulating Rad51 expression and DNA repair capacity in NSCLC cells.

Topics: Antineoplastic Agents; Benzoquinones; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; DNA Repair; Down-Regulation; Drug Synergism; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Lung Neoplasms; Rad51 Recombinase; RNA, Messenger; RNA, Small Interfering; Stilbenes

Chronic myelogenous leukemia (CML) is a myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This results in the expression of the Bcr-Abl fusion protein, a constitutively active protein tyrosine kinase. Although there are a few treatment options with Bcr-Abl kinase inhibitors, drug resistance is often encountered. One of the major obstacles in overcoming drug resistance in CML is the high endogenous levels of heat shock protein 70 (Hsp70). Resveratrol is a phytoalexin produced by several plants. We studied the chemotherapeutic effects and mode of action of resveratrol on K562 (CML) cells. Resveratrol induced apoptosis in K562 cells in a time-dependent manner. This was established by increased annexin V binding, corroborated with an enhanced caspase-3 activity and a rise in the sub-G(0)/G(1) population. Resveratrol treatment also caused suppression of Hsp70 both in mRNA and protein levels. The downregulation of Hsp70 by resveratrol exposure was correlated with a diminished presence of heat shock factor 1 (HSF1) in the nucleus, and the downregulation of transcriptional activity of HSF1. High endogenous levels of Hsp70 have been found to be a deterrent for sensitivity to chemotherapy. We show here that resveratrol could considerably enhance the apoptosis induction in K562 cells by 17-allylamino-17-demethoxygeldanamycin, an anticancer agent that inhibits Hsp90 but augments Hsp70 levels. We conclude that resveratrol significantly downregulated Hsp70 levels through inhibition of HSF1 transcriptional activity and appreciably augmented the pro-apoptotic effects of 17-allylamino-17-demethoxygeldanamycin.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzoquinones; Blotting, Western; Caspase 3; Cell Nucleus; DNA-Binding Proteins; Electrophoretic Mobility Shift Assay; Flow Cytometry; G1 Phase; Gene Expression Regulation, Neoplastic; Heat Shock Transcription Factors; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; K562 Cells; Lactams, Macrocyclic; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Promoter Regions, Genetic; Resting Phase, Cell Cycle; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleotide Reductases; RNA, Messenger; Stilbenes; Transcription Factors

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Benzoquinones; Bibenzyls; Diagnostic Imaging; Down-Regulation; ErbB Receptors; Gefitinib; Heterocyclic Compounds, 1-Ring; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Magnetic Resonance Imaging; Molecular Probe Techniques; Mutation; Neoplasms; Phthalazines; Physiological Phenomena; Positron-Emission Tomography; Protein Binding; Protein Kinase Inhibitors; Pyridines; Quinazolines; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-2; Receptors, Vascular Endothelial Growth Factor; Rifabutin; Stilbenes; Tissue Distribution; Trastuzumab