Suppression of tumor growth by designed dimeric epidithiodiketopiperazine targeting hypoxia-inducible transcription factor complex
Autor: | Jason B. Singh, Ramin Dubey, Jan E. Schnitzer, Bogdan Olenyuk, Lajos Szabo, Csaba F. László, Philip Oh, Swati Kushal, Michael D. Levin |
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Rok vydání: | 2013 |
Předmět: |
Models
Molecular Vascular Endothelial Growth Factor A Hypoxia-Inducible Factor 1 Lung Neoplasms Angiogenesis Transcription factor complex Mice Nude Antineoplastic Agents Breast Neoplasms Biochemistry Catalysis Piperazines Mice Colloid and Surface Chemistry Cell Line Tumor medicine Animals Humans p300-CBP Transcription Factors Breast Protein Interaction Maps Transcription factor Lung Regulation of gene expression Chemistry General Chemistry Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit Gene Expression Regulation Neoplastic Vascular endothelial growth factor A Cell culture Cancer research Female medicine.symptom Dimerization |
Zdroj: | Journal of the American Chemical Society. 135(11) |
ISSN: | 1520-5126 |
Popis: | Hypoxia is a hallmark of solid tumors, is associated with local invasion, metastatic spread, resistance to chemo- and radiotherapy, and is an independent, negative prognostic factor for a diverse range of malignant neoplasms. The cellular response to hypoxia is primarily mediated by a family of transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. Under normoxia, the oxygen-sensitive α subunit of HIF1 is rapidly and constitutively degraded but is stabilized and accumulates under hypoxia. Upon nuclear translocation, HIF1 controls the expression of over 100 genes involved in angiogenesis, altered energy metabolism, antiapoptotic, and pro-proliferative mechanisms that promote tumor growth. A designed transcriptional antagonist, dimeric epidithiodiketopiperazine (ETP 2), selectively disrupts the interaction of HIF1α with p300/CBP coactivators and downregulates the expression of hypoxia-inducible genes. ETP 2 was synthesized via a novel homo-oxidative coupling of the aliphatic primary carbons of the dithioacetal precursor. It effectively inhibits HIF1-induced activation of VEGFA, LOX, Glut1, and c-Met genes in a panel of cell lines representing breast and lung cancers. We observed an outstanding antitumor efficacy of both (±)-ETP 2 and meso-ETP 2 in a fully established breast carcinoma model by intravital microscopy. Treatment with either form of ETP 2 (1 mg/kg) resulted in a rapid regression of tumor growth that lasted for up to 14 days. These results suggest that inhibition of HIF1 transcriptional activity by designed dimeric ETPs could offer an innovative approach to cancer therapy with the potential to overcome hypoxia-induced tumor growth and resistance. |
Databáze: | OpenAIRE |
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