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Cycloprodigiosin hydrochloride, H + /CL – symporter, induces apoptosis and differentiation in HL‐60 cells
Author(s) -
Yamamoto Daigo,
Uemura Yoshiko,
Tanaka Kanji,
Nakai Koji,
Yamamoto Chizuko,
Takemoto Hiroto,
Kamata Keiko,
Hirata Hajime,
Hioki Koshiro
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20001001)88:1<121::aid-ijc19>3.0.co;2-c
Subject(s) - apoptosis , symporter , cancer research , chemistry , microbiology and biotechnology , hydrochloride , medicine , biology , biochemistry , gene , transporter
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. Int. J. Cancer 88:121–128, 2000. © 2000 Wiley‐Liss, Inc.