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Effect of the protein tyrosine kinase inhibitor genistein on normal and leukaemic haemopoietic progenitor cells
Author(s) -
CARLOSTELLA CARMELO,
REGAZZI ESTER,
GARAU DANIELA,
MANGONI LINA,
RIZZO MARIA TERESA,
BONATI ANTONIO,
DOTTI GIANPIETRO,
ALMICI CAMILLO,
RIZZOLI VITTORIO
Publication year - 1996
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.1996.d01-1694.x
Subject(s) - genistein , cfu gm , progenitor cell , peripheral blood mononuclear cell , haematopoiesis , biology , cd34 , tyrosine kinase , microbiology and biotechnology , bone marrow , leukemia , medicine , endocrinology , immunology , in vitro , stem cell , receptor , biochemistry
Receptor and nonreceptor protein tyrosine kinases (PTKs) play a key role in the control of normal and neoplastic cell growth. The availability of PTK inhibitors prompted us to evaluate the effects of genistein, a natural inhibitor of PTKs, on in vitro colony formation by normal multilineage colony‐forming units (CFU‐Mix), erythroid bursts (BFU‐E), granulocyte‐macrophage colony‐forming units (CFU‐GM), long‐term culture‐initiating cells (LTC‐IC) and acute myelogenous leukaemia colony‐forming units (CFU‐AML). Continuous exposure of normal marrow and blood mononuclear non‐adherent cells, blood CD34 + CD45RA − cells, and leukaemic blasts to increasing doses of genistein (1–100 μ M ) resulted in a statistically significant ( P ≤ 0.05) dose‐dependent suppression of CFU‐Mix, BFU‐E, CFU‐GM and CFU‐AML growth. Regression analysis showed that growth inhibition was linearly related to genistein concentration. Genistein dose causing 50% inhibition (ID 50 ) of CFU‐AML was significantly lower compared to CFU‐GM ID 50 for marrow (19 v 32 μ M P ≤0.017), unseparated blood (19 v 44 μ M P ≤ 0.028) or CD34 + CD45RA − blood (19 v 36, P ≤ 0.04). Preincubation of leukaemic blasts with genistein (200 μ M ) for 1–2 h confirmed that CFU‐AML were significantly more sensitive than normal marrow and blood CFU‐GM to genistein. Preincubation conditions which maximally suppressed leukaemic and normal colony growth spared a substantial percentage of marrow (29 ± 4%) and blood (40 ± 3%) LTC‐IC. In conclusion, our data demonstrate that: (a) genistein strongly inhibits the growth of normal and leukaemic haemopoietic progenitors; (b) growth inhibition is dose‐ and time‐dependent; (c) leukaemic progenitors are more sensitive than normal progenitors to genistein‐induced growth inhibition; (d) genistein exerts a direct toxic effect on haemopoietic cells while sparing a substantial proportion of LTC‐IC. The potent CFU‐AML growth inhibition associated with the relative resistance of normal LTC‐IC strongly supports the use of genistein for marrow purging.