Treatment-induced expression of anti-apoptotic proteins in WSU-CLL, a human chronic lymphocytic leukemia cell line.
Bryostatin 1 (bryo 1) has been shown to potentiate the anti-tumor activity of 2-chloro-2-deoxyadenosine (2-CdA) in chronic lymphocytic leukemia (CLL) and in the WSU-CLL cell line. However, like resistant CLL, WSU-CLL cells lose their sensitivity to bryo 1/2-CdA treatment. We report that 2-CdA-induced IAP expression may be a possible mechanism whereby resistance to apoptosis is acquired in these cells. In WSU-CLL cells, three members of the Inhibitors of Apoptosis (IAP) family were identified. Bryo 1 treatment of WSU-CLL cells leads to initiation of the apoptotic cascade and induced a marginal increase in XIAP protein expression. In contrast, 2-CdA treatment, alone or in combination with bryo 1, induced a substantial increase in survivin and XIAP proteins and phosphorylation of BAD. Bryo 1 alone induced caspase-7 and -9 dependent [poly ADP-ribose] polymerase (PARP) cleavage, while sequential treatment with bryo 1 (72 h) followed by 2-CdA (24 h) induced caspase-3,-7, and -9 dependent PARP cleavage and increased apoptosis. Although exposure to bryo 1 initiated apoptotic events, apoptosis was first enhanced by 2-CdA, and then reversed in a time-dependent manner by 2-CdA-induced expression of survival proteins. Taken together, resistance to bryo 1/2-CdA treatment may be the result of 2-CdA-induced IAP inhibition of the intrinsic apoptotic pathway caspases.
Wall
N R
NR
Department of Internal Medicine, Karmanos, Cancer Institute at Wayne State University School of Medicine, Detroit, Ml, 48201, USA.
Beck
F W
FW
Al-Katib
A M
AM
Mohammad
R M
RM
D015762:2-Chloroadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D054713:Bryostatins; D003839:Deoxyadenosines / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D018942:Macrolides; D008297:Male; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D000964:Antimetabolites, Antineoplastic; D054713:Bryostatins; D003839:Deoxyadenosines; D020536:Enzyme Activators; D007783:Lactones; D018942:Macrolides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D015762:2-Chloroadenosine; C046785:bryostatin 1; C055994:2-chloro-3'-deoxyadenosine