versipelostatin and Neoplasms

Topics: Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Humans; Macrolides; Molecular Chaperones; Neoplasms; Oligosaccharides; Oxazoles; Telomerase

Glucose deprivation, a cell condition that occurs in solid tumors, activates the unfolded protein response (UPR). A key feature of the UPR is the transcription program activation, which allows the cell to survive under stress conditions. Here, we show that the UPR transcription program is disrupted by the antidiabetic biguanides metformin, buformin, and phenformin depending on cellular glucose availability. These drugs inhibit production of the UPR transcription activators XBP1 and ATF4 and induce massive cell death during glucose deprivation as did the antitumor macrocyclic compound versipelostatin. Gene expression profiling shows remarkable similarity in the modes of action of biguanides and versipelostatin determined by the broad range of glucose deprivation-inducible genes. Importantly, during glucose deprivation, most of the biguanide suppression genes overlap with the genes induced by tunicamycin, a chemical UPR inducer. Gene expression profiling also identifies drug-driven signatures as a tool for discovering pharmacologic UPR modulators. Our findings show that disrupting the UPR during glucose deprivation could be an attractive approach for selective cancer cell killing and could provide a chemical genomic basis for developing UPR-targeting drugs against solid tumors.

Topics: Activating Transcription Factor 4; Cell Death; Cell Survival; DNA-Binding Proteins; Gene Expression Profiling; Genes, Reporter; Genomics; Glucose; Humans; Hypoglycemic Agents; Macrolides; Neoplasms; Oligosaccharides; Phenformin; Plasmids; Protein Denaturation; Protein Folding; Regulatory Factor X Transcription Factors; Transcription Factors; Transfection; X-Box Binding Protein 1

Topics: Animals; Antineoplastic Agents; Apoptosis; DNA Damage; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Glucose; Humans; Macrolides; Neoplasms; Oligosaccharides; Tumor Cells, Cultured

Glucose deprivation, a feature of poorly vascularized solid tumors, activates the unfolded protein response (UPR), a stress-signaling pathway, in tumor cells. We recently isolated a novel macrocyclic compound, versipelostatin (VST), that inhibits transcription from the promoter of GRP78, a gene that is activated as part of the UPR. We examined the effect of VST on the UPR induced by glucose deprivation or other stressors and on tumor growth in vivo.. Human colon cancer HT-29, fibrosarcoma HT1080, and stomach cancer MKN74 cells were cultured in the absence of glucose or in the presence of glucose and a UPR-inducing chemical stressor (the N-glycosylation inhibitor tunicamycin, the calcium ionophore A23187, or the hypoglycemia-mimicking agent 2-deoxyglucose [2DG]). The effect of VST on UPR induction was determined by reverse transcription-polymerase chain reaction and immunoblot analysis of the UPR target genes GRP78 and GRP94; by immunoblot analysis of the UPR transcriptional activators ATF6, XBP1, and ATF4; and by analyzing reporter gene expression in cells transiently transfected with a GRP78 promoter-reporter gene. Cell sensitivity to VST was examined with a colony formation assay and flow cytometry. In vivo antitumor activity of VST was assessed with an MKN74 xenograft model.. VST inhibited expression of UPR target genes in glucose-deprived or 2DG-treated cells but not in cells treated with tunicamycin or A23187. VST also inhibited the production of the UPR transcriptional activators XBP1 and ATF4 during glucose deprivation. The UPR-inhibitory action of VST was seen only in conditions of glucose deprivation and caused selective and massive killing of the glucose-deprived cells. VST alone and in combination with cisplatin statistically significantly (P =.004 and P<.001 for comparisons with untreated control, respectively) inhibited tumor growth of MKN74 xenografts.. Disruption of the UPR may provide a novel therapeutic approach to targeting glucose-deprived solid tumors.

Topics: Activating Transcription Factor 4; Activating Transcription Factor 6; Animals; Antineoplastic Agents; Cell Survival; Colonic Neoplasms; DNA-Binding Proteins; Endoplasmic Reticulum Chaperone BiP; Fibrosarcoma; Gene Expression Regulation, Neoplastic; Genes, Reporter; Glucose; Humans; Immunoblotting; Macrolides; Mice; Mice, Nude; Neoplasms; Nuclear Proteins; Oligosaccharides; Plasmids; Protein Folding; Regulatory Factor X Transcription Factors; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms; Streptomycetaceae; Trans-Activators; Transcription Factors; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured; X-Box Binding Protein 1