Flavopiridol induces apoptosis and caspase-3 activation of a newly characterized Burkitt's lymphoma cell line containing mutant p53 genes.
Burkitt's lymphoma cell lines have been important in vitro models for studying the pathogenesis of Burkitt's lymphoma (BL) and for exploring new treatment strategies. A new EBV(-) Burkitt's lymphoma cell line (GA-10) was established from a patient with a clinically aggressive, chemorefractory BL and characterized. Although functional p-glycoprotein could not be demonstrated by dye-efflux assays, both p53 genes were mutated in the GA-10 cells, perhaps contributing to the resistant phenotype of the original neoplasm. Two properties of BL cells which may be useful targets for novel cytotoxic therapeutics are their surface expression of CD77, the receptor for Shiga toxin (Stx), and their high rate of proliferation. Expression of CD77 on the GA-10 cells was heterogeneous in that certain subclones expressed high levels of CD77 and correspondingly exhibited strong growth inhibition by Stx while others showed low levels of CD77 expression and weak Stx-induced growth inhibition. Flavopiridol, a potent inhibitor of cell cycle progression through G1 and G2, induced cytotoxicity of the GA-10 cells with an LC(50) of approximately 40 nM vs 70 nM for HL-60 cells (P < 0.05). The concentrations of flavopiridol at which only 10% of the cells were viable (LC(10)) were approximately 280 nM for the GA-10 cells and 520 nM for the HL-60 cells (P < 0.05). Dose-related induction of apoptosis in response to flavopiridol was demonstrated in the GA-10 cells by morphology, TUNEL assay, and activation of caspase-3. Flavopiridol was also cytotoxic to seven other BL cell lines tested. These data suggest that flavopiridol may have therapeutic value in the treatment of Burkitt's lymphoma.
Rapoport
A P
AP
University of Maryland Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201, USA. arapoport@umm.edu
Simons-Evelyn
M
M
Chen
T
T
Sidell
R
R
Luhowskyj
S
S
Rosell
K
K
Obrig
T
T
Hicks
D
D
Hinkle
P M
PM
Nahm
M
M
Insel
R A
RA
Abboud
C N
CN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D022621:Shiga Toxin / Q000494:pharmacology; D014281:Trihexosylceramides / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000166:cytology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; D014281:Trihexosylceramides; C077990:alvocidib; C018549:globotriaosylceramide; D022621:Shiga Toxin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases