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Drug-Target Interaction

Drug

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PubChem ID:135411
Structure:
Synonyms:
125316-60-1
2-Naphthalenecarboxylic acid,
2-Naphthalenecarboxylic acid, 6-(4-hydroxy-3-tricyclo(3.3.1.1(3,7))dec-1-ylphenyl)-
6-(3-(1-adamantyl)-4-hydroxyphenyl)-2-naphthalenecarboxylic acid
6-(4-Hydroxy-3-tricyclo(3.3.1.1(3,7))dec-1-ylphenyl)-2-naphthalenecarboxylic acid
6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid
AHPN
C099555
C5865_SIGMA
Cd 437
CD-437
CD437
CD437 cpd
LS-94519
NCGC00092284-01
Ro 47-2077
Ro-47-2077

Target

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Uniprot ID:ICE_DROME
Synonyms:
Caspase
drICE
EC-Numbers:3.4.22.-
Organism:Drosophila melanogaster
Fruit fly
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
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References:

11423908
Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells.. Y Zang; R L Beard; R A Chandraratna; J X Kang (2001) Cell death and differentiation display abstract
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.