Overexpression of bcl-2 or bcl-XL fails to inhibit apoptosis mediated by a novel retinoid.
Overexpression of bcl-2 or bcl-XL has been found to inhibit the induction of apoptosis in malignant cells by a large number of agents including a wide variety of chemotherapeutic drugs. CD437 ¿6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphthalene carboxylic acid¿ is a novel retinoid that induces apoptosis in a number of malignant cells through a unique mechanism of action. The addition of 1 microM CD437 to HL-60/NEO cells resulted in capase 3 (CPP32) activation and poly(ADP-ribose) polymerase (PARP) cleavage in 3 h whereas in bcl-2- or bcl-XL-overexpressing HL-60 cells CD437 induced CPP32 activation and PARP cleavage in 6 h. Although 50 and 300 nM CD437 were required to induce PARP cleavage in HL-60/NEO and HL-60/bcl-2, HL-60/bcl-XL cells, respectively, maximal apoptosis in both cell lines was achieved utilizing 300 nM CD437. All three cell lines, however, share identical dose-response curves in terms of their growth inhibition, suggesting that CD437-mediated inhibition of growth and induction of apoptosis represent two distinct and separable processes. In addition, CD437 induces GI arrest as well as p21WAFI/CIPI mRNA expression in these cells despite the overexpression of bcl-2 or bcl-XL. CD437 induced mitochondrial instability as indicated by cytochrome c leakage into the cytoplasm in all three cell lines. CD437 also induced growth inhibition and apoptosis of an apoptosis-resistant variant of the HL-60 cell line (HCW-2), which switched expression from bcl-2 to bcl-XL. CD437-mediated apoptosis is not accompanied by downregulation of bcl-2 or bcl-XL or upregulation of bax. The reason for the inability of bcl-2 or bcl-XL overexpression to inhibit CD437-mediated apoptosis is unclear. The ability of CD437 to initiate apoptosis in a spectrum of malignant cells without interference from bcl-2 or bcl-XL overexpression suggests that CD437 may possess significant therapeutic potential in the treatment of malignancy.
Fontana
J A
JA
Department of Medicine, Marlene and Stewart Greenebaum Cancer Center, University of Maryland at Baltimore, USA.
Sun
R J
RJ
Rishi
A K
AK
Dawson
M I
MI
Ordónez
J V
JV
Zhang
Y
Y
Tschang
S H
SH
Bhalla
K
K
Han
Z
Z
Wyche
J
J
Poirer
G
G
Sheikh
M S
MS
Shroot
B
B
Reichert
U
U
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D003561:Cytarabine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012176:Retinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C099555:CD 437; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D012176:Retinoids; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003561:Cytarabine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases