Cycloprodigiosin hydrochloride, H(+)/CL(-) symporter, induces apoptosis and differentiation in HL-60 cells.
Cycloprodigiosin hydrochloride (cPrG * HCl), a novel H(+)/Cl(-) symporter, induces acidification of the cytosol and leads to apoptosis in rat and human liver cancer cells. In the present study, the effect of cPrG * HCl on a promyelocytic leukemia cell line (HL-60) was examined. cPrG * HCl lowered intracellular pH and induced apoptosis through up-regulation of Fas ligand, activation of stress-activated protein kinase (SAPK/JNK) and caspase. Apoptosis induced by cPrG * HCl was strongly suppressed when a cell-permeable weak base, imidazole, was present, indicating that cytosol acidification introduced by cPrG * HCl triggered caspase activation, leading to apoptosis. Concomitantly, cell differentiation into monocyte was also induced by cPrG * HCl both morphologically and functionally. However, the cPrG * HCl-induced differentiation was not suppressed by addition of imidazole, indicating that the differentiation process is unrelated to cytosol acidification. Further, the differentiation induced by cPrG * HCl was blocked by tyrosine kinase inhibitors (lavendustin A and HMA) but unaffected by the inhibitors of A-kinase (H-89) or C-kinase (H-7). Taken together, these findings suggest that cPrG * HCl, through apoptosis and differentiation induction, may be useful in leukemia treatment.
Yamamoto
D
D
Department of Surgery II, Kansai Medical University, Moriguchi, Osaka, Japan. yammamotd@takii.kmu.ac.jp
Uemura
Y
Y
Tanaka
K
K
Nakai
K
K
Yamamoto
C
C
Takemoto
H
H
Kamata
K
K
Hirata
H
H
Hioki
K
K
D017920:Antiporters / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*
D017920:Antiporters; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D007211:Indoles; D008562:Membrane Glycoproteins; D011758:Pyrroles; C114260:hydrogen-chloride symporter; C108328:cycloprodigiosin; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases