1. Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies.
- Author
-
Liang D, Li L, Lynch C, Mackowiak B, Hedrich WD, Ai Y, Yin Y, Heyward S, Xia M, Wang H, and Xue F
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Constitutive Androstane Receptor, Cyclophosphamide chemical synthesis, Cyclophosphamide chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Hep G2 Cells, Humans, Lymphoma, Non-Hodgkin metabolism, Lymphoma, Non-Hodgkin pathology, Molecular Structure, Prodrugs chemical synthesis, Prodrugs chemistry, Receptors, Cytoplasmic and Nuclear metabolism, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Cyclophosphamide pharmacology, Lymphoma, Non-Hodgkin drug therapy, Prodrugs pharmacology, Receptors, Cytoplasmic and Nuclear agonists
- Abstract
The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC
50 value of 0.66 μM and EMAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF