title: Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells.
abstract: Protein kinase C (PKC) plays an important role in the proliferation and differentiation of various cell types including normal and leukemic hematopoietic cells. Recently, various PKC modulators were used as a chemotherapeutic agent of leukemia. Decursin (1), a pyranocoumarin from Angelica gigas, exhibits the cytotoxic effects on various human cancer cell lines and in vitro PKC activation. For the development of more effective anticancer agents with PKC modulation activity, 11 decursin derivatives 2-12 were chemically synthesized and evaluated for their ability to act as a tumor-suppressing PKC activator and as an antagonist to phorbol 12-myristate 13-acetate (PMA), a tumor-promoting PKC activator. In the presence of phosphatidylserine (PS), all of 12 compounds 1-12 activated PKC (mainly alpha, beta, and gamma isozymes) but only three compounds 1-3 activated PKC even in the absence of PS. Six compounds 1-6 containing the coumarin structure were cytotoxic to human K562 erythroleukemia and U937 myeloleukemia cells. A cytotoxic mechanism of decursin and its derivatives was investigated using TUR cells, a PKC betaII-deficient variant of U937 cells. Among six compounds 1-6 with cytotoxicity to K562 and U937 leukemia cells, only three compounds 1-3 were cytotoxic to TUR cells. Therefore, compounds 1-3 and 4-6 inhibit the proliferation of leukemia cells in a PKC betaII-independent and dependent manner, respectively, indicating that the side chain of compounds determines the dependency of their cytotoxicity on PKC betaII. To further elucidate the cytotoxic mechanism of compounds 1 and 2, levels of PKC isozymes and generation of reactive oxygen species (ROS) were investigated. Compounds 1-2 induced the down-regulation of PKC alpha and betaII in K562 cells and the production of ROS in U937 cells. Thus, PKC and ROS are probably important factors in the cytotoxic mechanism of compounds 1-2. From these results, the structure-activity relationship of decursin and its derivatives is as follows: (i) the coumarin structure is required for anti-leukemic activity and (ii) the side chain is a determinant of PKC activation and the cytotoxic mechanism in leukemia cells.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea.
authors.forename: Hyeon Ho
authors.initials: HH
authors.lastname: Kim
authors.forename: Sung
authors.initials: S
authors.lastname: Sik Bang
authors.forename: Jin
authors.initials: J
authors.lastname: Seok Choi
authors.forename: Hogyu
authors.initials: H
authors.lastname: Han
authors.forename: Ik-Hwan
authors.initials: IH
authors.lastname: Kim
mesh_terms: D029969:Angelica / Q000737:chemistry; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002087:Butyrates / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D010936:Plant Extracts; D011493:Protein Kinase C / Q000502:physiology*; D017382:Reactive Oxygen Species; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D001578:Benzopyrans; D002087:Butyrates; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C101278:decursin; D011493:Protein Kinase C