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. Int. J. Cancer 88:121–128, 2000. © 2000 Wiley‐Liss, Inc.

Characterization of Bacterium Isolated from the Sediment at Coastal Area of Omura Bay in Japan and Several Biological Activities of Pigment Produced by This Isolate

“…The red pigment, RP-063, showed similarity to prodigiosin in its physical properties, such as insolubility in water and the absorption spectrum of RP-063 with the maximum absorbance at 533 nm, relatively corresponding with the maximum absorption of prodigiosin and undecylprodigiosin at 540 and 528 nm, respectively (1,9). In addition, in our preliminary experiments, RP-063 was similar to prodigiosin (25) rather than cycloprodigiosin hydrochloride (41) in biological activities such as induction of apoptotic cell death via p38 MAP kinase activation and disorder of intracellular acidic compartment in human monocytic U937 cells (data not shown). Therefore, it was suggested that RP-063 is a red pigment which belongs to the prodigiosin family.…”

Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia

“…2 Prodigiosin also induces apoptosis in cells derived from other human tumors. 3,4 Cycloprodigiosin, another member of the prodigiosin family, induces apoptosis in various cancer cell lines including acute human T-cell leukemia, 17 promyelocytic leukemia, 18 human and rat hepatocellular cancer, 19 human breast cancer, 20 and TNF-stimulated human cervix carcinoma (HeLa). 21 The National Cancer Institute (Bethesda) has also shown that prodigiosin has an average IC 50 of 2.1 mM against a panel of 57 different human cancer cell lines (this information is available on the Internet at www.dtp.nci.nih.gov the NSC number for prodigiosin is 47147-F).…”

“…This activity has been implicated in cycloprodigiosin-induced apoptosis because imidazole inhibits both acidification and apoptosis in different human cancer cell lines. [18][19][20] The role of cytoplasmic acidification in the apoptosis of B-CLL cells will be analyzed in the future.…”

Prodigiosin and its potential applications

“…Also, prodigiosins promoted H+/Cl-, a symport activity leading to acidification of the cytosol. This activity was implicated in cycloprodigiosin-induced apoptosis because imidazole inhibited both acidification and apoptosis in different human cancer cell lines (Yamamoto et al 1999;Yamamoto et al 2000).…”