AI Article Synopsis
- Cyclophosphamide (CPA) is a commonly used prodrug for cancer treatment, which gets activated by the enzyme cytochrome P450 2B6 (CYP2B6), regulated by the human constitutive androstane receptor (hCAR).* -
- The compound CITCO is a known hCAR agonist that enhances CPA's effectiveness; however, researchers developed a new compound, DL5016, which is even more potent in activating hCAR.* -
- DL5016 significantly increases the expression of CYP2B6 and enhances CPA's cytotoxic effects on non-Hodgkin lymphoma cells, indicating its potential as a sensitizer in cancer therapies.*
Article 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 value of 0.66 μM and E 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718324 | PMC |
| http://dx.doi.org/10.1016/j.ejmech.2019.06.031 | DOI Listing |
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