ABSTRACT
A novel series of oxime ligands has been synthesized that displays potent, specific activation of the retinoid X receptors (RXRs). The oximes of 3-substituted (tetramethyltetrahydronaphthyl)carbonylbenzoic acids are readily available by condensation with hydroxyl- or methoxylamine; alkylation of the hydroxyl oxime provides a variety of analogues. Oximes and variously substituted oxime derivatives demonstrate high binding affinity for the RXRs and specific RXR activation and, hence, are called rexinoids. These oxime rexinoids are activators of the RXR:PPARgamma heterodimer and are potent inducers of differentiation of 3T3-L1 preadipocytes to adipocytes. We have recently reported that ligands which activate the RXR:PPARgamma heterodimer in this manner are effective in the treatment of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Thus, these new oxime rexinoids are potential therapeutic agents for the treatment of metabolic disorders, such as obesity and diabetes.
Subject(s)
Adipocytes/drug effects , Benzoates/chemical synthesis , DNA-Binding Proteins/metabolism , Oximes/chemical synthesis , Receptors, Retinoic Acid/agonists , Transcription Factors/agonists , 3T3 Cells , Adipocytes/metabolism , Adipocytes/physiology , Animals , Benzoates/chemistry , Benzoates/metabolism , Benzoates/pharmacology , Binding, Competitive , Cell Differentiation/drug effects , Cell Line , Crystallography, X-Ray , Ligands , Mice , Oximes/chemistry , Oximes/metabolism , Oximes/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Retinoic Acid/biosynthesis , Receptors, Retinoic Acid/metabolism , Recombinant Proteins/agonists , Recombinant Proteins/biosynthesis , Recombinant Proteins/metabolism , Retinoid X Receptors , Transcription Factors/biosynthesis , Transcription Factors/metabolism , Transfection , Triglycerides/metabolismABSTRACT
BACKGROUND: Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic leukemia (APL). We evaluated this drug in patients with APL in an attempt to elucidate its mechanism of action. METHODS: Twelve patients with APL who had relapsed after extensive prior therapy were treated with arsenic trioxide at doses ranging from 0.06 to 0.2 mg per kilogram of body weight per day until visible leukemic cells were eliminated from the bone marrow. Bone marrow mononuclear cells were serially monitored by flow cytometry for immunophenotype, fluorescence in situ hybridization, reverse-transcription-polymerase-chain-reaction (RT-PCR) assay for PML-RAR-alpha fusion transcripts, and Western blot analysis for expression of the apoptosis-associated proteins caspases 1, 2, and 3. RESULTS: Of the 12 patients studied, 11 achieved complete remission after treatment that lasted from 12 to 39 days (range of cumulative doses, 160 to 495 mg). Adverse effects were relatively mild and included rash, lightheadedness, fatigue, and musculoskeletal pain. Cells that expressed both CD11b and CD33 (antigens characteristic of mature and immature cells, respectively), and which were found by fluorescence in situ hybridization to carry the t(15;17) translocation, increased progressively in number during treatment and persisted in the early phase of complete remission. Eight of 11 patients who initially tested positive for the PML-RAR-alpha fusion transcript by the RT-PCR assay later tested negative; 3 other patients, who persistently tested positive, relapsed early. Arsenic trioxide induced the expression of the proenzymes of caspase 2 and caspase 3 and activation of both caspase 1 and caspase 3. CONCLUSIONS: Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed. The clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adolescent , Adult , Aged , Antigens, CD/analysis , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Apoptosis , Arsenic Trioxide , Arsenicals/administration & dosage , Arsenicals/adverse effects , Bone Marrow Cells/immunology , Caspases , Cell Differentiation , Child , Humans , Immunophenotyping , Leukemia, Promyelocytic, Acute/immunology , Leukemia, Promyelocytic, Acute/pathology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Middle Aged , Neoplasm Proteins/analysis , Neoplasm Proteins/drug effects , Oncogene Proteins, Fusion/analysis , Oncogene Proteins, Fusion/drug effects , Oxides/administration & dosage , Oxides/adverse effects , Recurrence , Remission Induction/methodsABSTRACT
Retinoid X receptor (RXR) plays a central role in the regulation of many intracellular receptor signalling pathways and can mediate ligand-dependent transcription, acting as a homodimer or as a heterodimer. Here we identify an antagonist towards RXR homodimers which also functions as an agonist when RXR is paired as a heterodimer to specific partners, including peroxisome proliferator-activated receptor and retinoic acid receptor. This dimer-selective ligand confers differential interactions on the transcription machinery: the antagonist promotes association with TAF110 (TATA-binding protein (TBP)-associated factor 110) and the co-repressor SMRT, but not with TBP, and these properties are distinct from pure RXR agonists. This unique class of RXR ligands will provide a means to control distinct target genes at the level of transcription and allow the development of retinoids with a new pharmacological action.
