Cycloprodigiosin hydrochloride, H(+)/CL(-) symporter, induces apoptosis and differentiation in HL-60 cells.

Abstract

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.

• Authors: D Yamamoto, Y Uemura, K Tanaka, K Nakai, C Yamamoto, H Takemoto, K Kamata, H Hirata, K Hioki
• Journal: International journal of cancer (Int J Cancer) Vol. 88 Issue 1 Pg. 121-8 (Oct 01 2000) ISSN: 0020-7136 [Print] United States
• PMID: 10962449 (Publication Type: Journal Article)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• Antiporters
• FASLG protein, human
• Fas Ligand Protein
• Faslg protein, rat
• Indoles
• Membrane Glycoproteins
• Pyrroles
• hydrogen-chloride symporter
• cycloprodigiosin
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases
• Caspases

Topics

• Antiporters (pharmacology)
• Apoptosis (drug effects, physiology)
• Caspases (metabolism)
• Cell Differentiation (drug effects)
• Cell Division (drug effects)
• Enzyme Activation
• Fas Ligand Protein
• HL-60 Cells (cytology, drug effects)
• Humans
• Hydrogen-Ion Concentration
• Indoles (pharmacology)
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• MAP Kinase Signaling System (drug effects, physiology)
• Membrane Glycoproteins (biosynthesis, physiology)
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Pyrroles (pharmacology)