Investigation of anticancer mechanism of clavulone II, a coral cyclopentenone prostaglandin analog, in human acute promyelocytic leukemia.
The marine prostanoid clavulones were shown to exert cytotoxicity against several cancer cells. In the present study, we illustrate the pathways utilized by clavulone II to trigger apoptotic signaling in human acute promyelocytic leukemia HL-60 cells. Exposure of cells to clavulone II resulted in early induction of phosphatidylserine externalization, mitochondrial dysfunction, and alteration of the cell cycle. Down-regulated expression of cyclin D1 explained the effect of clavulone II on G1 phase arrest of the cell cycle. Clavulone II induced the disruption of mitochondrial membrane potential and activation of caspase-8, -9 and -3 in a time- and concentration-dependent manner. Furthermore, the effect of 3 microM clavulone II was accompanied by the up-regulation of Bax, down-regulation of Mcl-1, and cleavage of Bid. Taken together, it is suggested that low concentrations of clavulone II induce the antiproliferative effect through the down-regulation of cyclin D1 expression and G1 arrest of the cell cycle, while that of high concentration induce the apoptotic cell death via the modulation of members of caspases and Bcl-2 family proteins in HL-60 cells.
Huang
Yu-Chun
YC
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
Guh
Jih-Hwa
JH
Shen
Ya-Ching
YC
Teng
Che-Ming
CM
D000818:Animals; D037421:Anthozoa; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002469:Cell Separation; D019938:Cyclin D1 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D016193:G1 Phase; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007425:Intracellular Membranes / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008564:Membrane Potentials; D008956:Models, Chemical; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011453:Prostaglandins / Q000737:chemistry*; D011454:Prostaglandins A / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D000970:Antineoplastic Agents; D011453:Prostaglandins; D011454:Prostaglandins A; D019253:Proto-Oncogene Proteins c-bcl-2; D019938:Cyclin D1; C057741:clavulone II; D004247:DNA; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases