4-hydroperoxy Cyclophosphamide, the active metabolite of cyclophosphamide, can cross-link DNA and induce T cell apoptosis independently of caspase receptor activation. It also activates the mitochondrial death pathway through the production of reactive oxygen species (ROS). 4-hydroperoxy Cyclophosphamide is useful in research on rheumatoid arthritis and autoimmune diseases[1-2].
4-hydroperoxy Cyclophosphamide(1 μg/mL, 72-96 h), along with methotrexate, suppresses RANKL expression in IL-6/sIL-6R-stimulated fibroblast-like synoviocytes by inhibiting the JAK2/STAT3 and p38MAPK signaling pathways[3]. 4-hydroperoxy Cyclophosphamide (3 μg/ml; 48h) treatment resulted in the production of reactive oxygen species, increased levels of Bax, and the translocation of mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (EndoG) to the nucleus. This treatment causes caspase-independent cell death in human CTL [4].
4-hydroperoxy Cyclophosphamide (200 mg/kg; i.p; 5 days) induced caspase-independent cell death in mouse T cells and B cells[4]. 4-hydroperoxy Cyclophosphamide (50-200 μg) intradermal injection at the sensitized site in guinea pig models of in-vivo contact sensitivity resulted in a significant enhancement of contact hypersensitivity [5].
References:
[1]. Fleer R, Brendel M. Toxicity, interstrand cross-links and DNA fragmentation induced by 'activated' cyclophosphamide in yeast: comparative studies on 4-hydroperoxy-cyclophosphamide, its monofunctional analogon, acrolein, phosphoramide mustard, and nor-nitrogen mustard. Chem Biol Interact. 1982 Mar 1;39(1):1-15. doi: 10.1016/0009-2797(82)90002-3. PMID: 7037214.
[2]. Chen Y, Ai L, et,al. The EZH2-H3K27me3 axis modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury. Cell Death Discov. 2023 Nov 14;9(1):413. doi: 10.1038/s41420-023-01705-6. PMID: 37963880; PMCID: PMC10646043.
[3]. Niu HQ, Zhao WP, et,al. Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via suppression of the JAK2/STAT3 and p38MAPK signaling pathway. Int Immunopharmacol. 2018 Aug;61:45-53. doi: 10.1016/j.intimp.2018.05.014. Epub 2018 May 24. PMID: 29803913.
[4]. Strauss G, Westhoff MA, et,al. 4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG. Cell Death Differ. 2008 Feb;15(2):332-43. doi: 10.1038/sj.cdd.4402272. Epub 2007 Nov 23. PMID: 18034189.
[5]. Boerrigter GH, de Groot J, et,al. Intradermal administration of 4-hydroperoxy-cyclophosphamide during contact sensitization potentiates effector T cell responsiveness in draining lymph nodes. Immunopharmacology. 1986 Feb;11(1):13-20. doi: 10.1016/0162-3109(86)90060-3. PMID: 3485619.