Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells.

Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Research Abstract Details 

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Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Abstract Text:

Y Zang,R L Beard,R A Chandraratna,J X Kang,

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid (AHPN/CD437) has been proven to be a potent inducer of apoptosis in a variety of tumor cell types. However, the mechanism of its action remains to be elucidated. Recent studies suggest that the lysosomal protease cathepsin D, when released from lysosomes to the cytosol, can initiate apoptosis. In this study, we examined whether cathepsin D and free radicals are involved in the CD437-induced apoptosis. Exposure of human leukemia HL-60 cells to CD437 resulted in rapid induction of apoptosis as indicated by caspase activation, phosphatidylserine exposure, mitochondrial alterations and morphological changes. Addition of the antioxidants alpha-tocopherol acetate effectively inhibited the CD437-induced apoptosis. Measurement of the intracellular free radicals indicated a rise in oxidative stress in CD437-treated cells, which could be attenuated by alpha-tocopherol acetate. Interestingly, pretreatment of cells with the cathepsin D inhibitor pepstatin A blocked the CD437-induced free radical formation and apoptotic effects, suggesting the involvement of cathepsin D. However, Western blotting revealed no difference in cellular quantity of any forms of cathepsin D between control cells and CD437-treated cells, whereas immunofluorescence analysis of the intracellular distribution of cathepsin D showed release of the enzyme from lysosomes to the cytosol. Labeling of lysosomes with lysosomotropic probes confirmed that CD437 could induce lysosomal leakage. The CD437-induced relocation of cathepsin D could not be prevented by alpha-tocopherol acetate, suggesting that the lysosomal leakage precedes free radical formation. Furthermore, a retinoic acid nuclear receptor (RAR) antagonist failed to block these effects of CD437, suggesting that the action of CD437 is RAR-independent. Taken together, these data suggest a novel lysosomal pathway for CD437-induced apoptosis, in which lysosomes are the primary target and cathepsin D and free radicals act as death mediators.

Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Publishing Authors By Initials

Y Zang,RL Beard,RA Chandraratna,JX Kang,

For similar heterocyclic compounds: heterocyclic compounds, 2-ring: benzopyrans: vitamin e: tocopherols: alpha-tocopherol research abstracts see: heterocyclic compounds: heterocyclic compounds, 2-ring: benzopyrans: vitamin e: tocopherols: alpha-tocopherol research

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Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Cell death and differentiation

VOLUME: 8

Page Numbers: 477-85

Journal Abbreviation: Cell Death Differ.

ISSN: 1350-9047

DAY: 19

MONTH: May

YEAR: 2001

Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9437445

Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Keywords Mesh Terms:

KEYWORDS: alpha-Tocopherol

MESH TERMS: analogs & derivatives

Chemical & Substance for Abstract: Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. Information

Substance Name: Cathepsin D

Registry Number: EC 3.4.23.5

Grant and Affiliation Information for Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells.

AFFILIATION: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Country: England

AGENCY: United States NCI

GRANT: CA-79553

ACRONYM: CA

MEDLINETA: Cell Death Differ

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