Abrogation of mitochondrial cytochrome c release and caspase-3 activation in acquired multidrug resistance.
Acquired multidrug resistance to anti-cancer agents has been associated with overexpression of the P-glycoprotein and other members of the ATP-binding cassette superfamily. The present studies demonstrate that SCC-25 cells selected for resistance to the alkylating agent cisplatin (CDDP) overexpress the anti-apoptotic Bcl-xL protein. In contrast to parental cells, the SCC-25/CDDP-resistant variant failed to exhibit activation of caspase-3, cleavage of protein kinase C delta, and other characteristics of apoptosis in response to CDDP. Similar results were obtained when SCC-25/CDDP cells were exposed to the structurally and functionally unrelated antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C). Other cells selected for resistance to doxorubicin or vincristine also exhibited overexpression of Bcl-xL and failed to respond to CDDP and ara-C with activation of caspase-3. The results further demonstrate that multidrug-resistant cells exhibit a block in the release of mitochondrial cytochrome c into the cytosol and that this effect is dependent on overexpression of Bcl-xL. The demonstration that lysates from the resistant cells respond to the addition of cytochrome c with activation of caspase-3 confirms that the block in apoptosis is because of inhibition of mitochondrial cytochrome c release. These findings demonstrate that cells respond to diverse classes of anti-cancer drugs with overexpression of Bcl-xL and that this response represents another mechanism of acquired multidrug resistance.
Kojima
H
H
Department of Otolaryngology, The Jikei University School of Medicine, Tokyo 105, Japan.
Endo
K
K
Moriyama
H
H
Tanaka
Y
Y
Alnemri
E S
ES
Slapak
C A
CA
Teicher
B
B
Kufe
D
D
Datta
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003561:Cytarabine / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003561:Cytarabine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D002945:Cisplatin