ABSTRACT
Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene. BET inhibitor treatment prevented this interaction, leading to a dramatic reduction of PGC-1α expression. Accordingly, BET inhibition diminished respiration and mitochondrial function in cells. In vivo, melanoma models with high PGC-1α expression strongly responded to BET inhibition by reduction of PGC-1α and impaired tumor growth. Altogether, our findings identify epigenetic regulatory elements that define a subset of melanomas with high sensitivity to BET inhibition, which opens up the opportunity to define melanoma patients most likely to respond to this treatment, depending on their tumor characteristics.
Subject(s)
Antineoplastic Agents/pharmacology , Enhancer Elements, Genetic/genetics , Melanoma/genetics , Nuclear Proteins/antagonists & inhibitors , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Transcription Factors/antagonists & inhibitors , Animals , Antineoplastic Agents/therapeutic use , Azepines/pharmacology , Azepines/therapeutic use , Benzodiazepines/pharmacology , Benzodiazepines/therapeutic use , Cell Cycle Proteins , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic , Female , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Melanoma/drug therapy , Melanoma/pathology , Mice , Mice, Inbred C57BL , Mice, Nude , Mitochondria/drug effects , Mitochondria/metabolism , Nuclear Proteins/metabolism , Patient Selection , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Protein Binding/genetics , SOXE Transcription Factors/genetics , SOXE Transcription Factors/metabolism , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Transcription Factors/metabolism , Treatment Outcome , Triazoles/pharmacology , Triazoles/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
The natural product hybrids quinone-mucocin and quinone- squamocin D were synthesized. In these hybrids, the butenolide unit of the annonaceous acetogenins mucocin and squamocin D is exchanged for the quinone moiety of the natural complex I substrate ubiquinone. For both syntheses, a modular, highly convergent approach was applied. Quinone-mucocin was constructed out of a tetrahydropyran (THP) component 1, a tetrahydrofuran (THF) unit 2, and a quinone precursor 3. A stereoselective, organometallic coupling reaction was chosen for the addition of the THP unit to the rest of the molecule. In the final step, the oxidation to the free quinone was achieved by using cerium(IV) ammonium nitrate (CAN) as the oxidizing agent. Quinone-squamocin D was assembled in a similar manner, from the chiral side chain bromide 16, the central bis-THF core 17, and the quinone precursor 18. Inhibition of complex I (isolated from bovine heart mitochondria) by the quinone acetogenins and several smaller building blocks was examined; quinone mucocin and quinone-squamocin D act as strong inhibitors of complex I. These results and the data from the smaller substructures indicate that other substructures of the acetogenins besides the butenolide group, such as the polyether component and the lipophilic left-hand side chain, are necessary for the strong binding of the acetogenins to complex I.
Subject(s)
Benzoquinones/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Lactones/chemistry , Lactones/chemical synthesis , Lactones/pharmacology , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Pyrans/chemistry , Pyrans/chemical synthesis , Pyrans/pharmacology , Quinones/chemical synthesis , Quinones/pharmacology , Animals , Benzoquinones/pharmacology , Cattle , Electron Transport Complex I , Furans/chemistry , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolismABSTRACT
A total synthesis of the Annonaceous acetogenin mucocin has been accomplished. The synthesis follows a convergent strategy, wherein at a very late stage the left part of the molecule is connected with the right part. The key reaction is the stereocontrolled addition of an organomagnesium compound 2 to the aldehyde 3. The THP ring of mucocin is build by a 6-endo epoxide cyclization of an epoxyacetonide precursor (16 --> 17). The new modular synthetic approach developed herein should be useful for the synthesis of other related natural products as well as pharmacologically interesting analogues.
