Abstract
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 (1-100μM) 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 (ID50) of CFU-AML was significantly lower compared to CFU-GM ID50 for marrow (19 v 32μM, P ≤0.017), unseparated blood (19 v 44μM, P ≤ 0.028) or CD344+CD45RA- blood (19 v 36, P≤0.04). Preincubation of leukaemic blasts with genistein (200μM) 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.
| Original language | English |
|---|---|
| Pages (from-to) | 551-557 |
| Number of pages | 7 |
| Journal | British Journal of Haematology |
| Volume | 93 |
| Issue number | 3 |
| Publication status | Published - 1996 |
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Keywords
- Genistein
- LTC-IC
- Marrow purging
- Progenitor cells
- Protein-tyrosine kinases
ASJC Scopus subject areas
- Hematology
Cite this
Effect of the protein tyrosine kinase inhibitor genistein on normal and leukaemic haemopoietic progenitor cells. / Carlo-Stella, Carmelo; Regazzi, Ester; Garau, Daniela; Mangoni, Lina; Rizzo, Maria Teresa; Bonati, Antonio; Dotti, Gianpietro; Almici, Camillo; Rizzoli, Vittorio.
In: British Journal of Haematology, Vol. 93, No. 3, 1996, p. 551-557.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Effect of the protein tyrosine kinase inhibitor genistein on normal and leukaemic haemopoietic progenitor cells
AU - Carlo-Stella, Carmelo
AU - Regazzi, Ester
AU - Garau, Daniela
AU - Mangoni, Lina
AU - Rizzo, Maria Teresa
AU - Bonati, Antonio
AU - Dotti, Gianpietro
AU - Almici, Camillo
AU - Rizzoli, Vittorio
PY - 1996
Y1 - 1996
N2 - 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 (1-100μM) 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 (ID50) of CFU-AML was significantly lower compared to CFU-GM ID50 for marrow (19 v 32μM, P ≤0.017), unseparated blood (19 v 44μM, P ≤ 0.028) or CD344+CD45RA- blood (19 v 36, P≤0.04). Preincubation of leukaemic blasts with genistein (200μM) 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.
AB - 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 (1-100μM) 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 (ID50) of CFU-AML was significantly lower compared to CFU-GM ID50 for marrow (19 v 32μM, P ≤0.017), unseparated blood (19 v 44μM, P ≤ 0.028) or CD344+CD45RA- blood (19 v 36, P≤0.04). Preincubation of leukaemic blasts with genistein (200μM) 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.
KW - Genistein
KW - LTC-IC
KW - Marrow purging
KW - Progenitor cells
KW - Protein-tyrosine kinases
UR - http://www.scopus.com/inward/record.url?scp=0029949993&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029949993&partnerID=8YFLogxK
M3 - Article
C2 - 8652372
AN - SCOPUS:0029949993
VL - 93
SP - 551
EP - 557
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
IS - 3
ER -