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 study ing the pathogenesis of Burkitt's lymphoma (BL) and for exploring new treat ment strategies. A new EBV(-) Burkitt's lymphoma cell line (GA-10) was esta blished from a patient with a clinically aggressive, chemorefractory BL and characterized. Although functional p-glycoprotein could not be demonstrate d by dye-efflux assays, both p53 genes were mutated in the GA-10 cells, per haps contributing to the resistant phenotype of the original neoplasm. Two properties of BL cells which may be useful targets for novel cytotoxic ther apeutics 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 in hibition. Flavopiridol, a potent inhibitor of cell cycle progression throug h G1 and G2, induced cytotoxicity of the GA-10 cells with an LC50 of approx imately 40 nM vs 70 nM for HL-60 cells (P < 0.05). The concentrations of fl avopiridol at which only 10% of the cells were viable (LC10) were approxima tely 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 demonst rated in the GA-10 cells by morphology, TUNEL assay, and activation of casp ase-3. Flavopiridol was also cytotoxic to seven other BL cell lines tested. These data suggest that flavopiridol may have therapeutic value in the tre atment of Burkitt's lymphoma. (C) 2001 Academic Press.