Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases

Uckun, Fatih M.; We, Evans; Forsyth, C. F.; Waddick, KG; Ahlgren, LT; Chelstrom, Lisa M.; Burkhardt, Anne L.; Bolen, Joseph B.; Myers, Dorothea E.

doi:10.1126/science.7531365

Cited by 258 publications

(130 citation statements)

References 55 publications

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“…A maximum 20-fold increase in VSMC DNA synthesis was observed with 0.1 unit/ml thrombin, a result that indicates that thrombin is capable of causing growth in VSMC. To determine whether thrombin-stimulated DNA synthesis requires proteintyrosine kinase activity, growth-arrested VSMC were treated with thrombin (0.1 unit/ml) in the presence and absence of 25 M genistein and/or 1 M herbimycin A, two structurally different but potent protein-tyrosine kinase inhibitors (23,24), and DNA synthesis was measured. Genistein inhibits receptor and non-receptor type protein-tyrosine kinase activity by competing with ATP (25), while herbimycin A inhibits cellular protein-tyrosine kinase activities, such as Src irreversibly by a mechanism involving interactions of benzoquinone with protein sulfhydryl groups (26).…”

Section: Resultsmentioning

confidence: 99%

Thrombin Stimulates Phosphorylation of Insulin-like Growth Factor-1 Receptor, Insulin Receptor Substrate-1, and Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells

Rao

Delafontaine²,

Runge

1995

Journal of Biological Chemistry

135

101

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It has recently been reported that protein-tyrosine kinase activity is required for thrombin-induced growth in vascular smooth muscle cells (VSMC). In the present study, we have identified several phosphoproteins that are tyrosine-phosphorylated in response to thrombin in quiescent VSMC. These proteins are insulin-like growth factor-1 receptor ␤-subunit (IGF-IR␤), insulin receptor substrate-1 (IRS-1), and phospholipase C-␥1 (PLC-␥1). Thrombin-stimulated phosphorylation of these proteins was rapid; it was maximal at 1 min and reduced thereafter. Thrombin also activated mitogen-activated protein kinases (MAPK) in quiescent VSMC in a biphasic manner with a rapid and larger peak at 10 min (6-fold) followed by a sustained smaller second peak at 2 h (2-fold). Inhibition of protein-tyrosine kinase activity by the use of two structurally different protein-tyrosine kinase inhibitors, genistein and herbimycin A, significantly blocked the thrombin-induced tyrosine phosphorylation of IGF-1R␤, IRS-1, and PLC-␥1 and decreased thrombin-stimulated DNA synthesis. In contrast, however, inhibition of protein-tyrosine kinase activity had no effect on thrombin activation of MAPK. Collectively, these findings suggest a role for tyrosine phosphorylation of IGF-IR␤, IRS-1, and PLC-␥1 in thrombin-induced mitogenic signaling events in VSMC. Furthermore, while protein tyrosine phosphorylation is essential for thrombin-induced DNA synthesis, it is not required for thrombin-stimulated MAPK activation. Since thrombin rapidly activated Src in VSMC, Src may be involved in the cross-talk between the G-protein-coupled receptor agonist and a tyrosine kinase receptor such as IGF-1R.

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Section: Resultsmentioning

confidence: 99%

Thrombin Stimulates Phosphorylation of Insulin-like Growth Factor-1 Receptor, Insulin Receptor Substrate-1, and Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells

Rao

Delafontaine²,

Runge

1995

Journal of Biological Chemistry

135

101

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“…It has been reported that genistein is a potent inhibitor of cell proliferation, oncogenesis and clonogenic ability in animal and human cells (Fotsis et al, 1995;Barnes, 1995). Genistein also inhibits the growth of carcinogeninduced cancers in rats and human leukemia cells transplanted into mice (Lamartiniere et al, 1995;Uckun et al, 1995). The induction of stress proteins (e.g.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein

et al. 1999

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Breast cancer is the most common cancer among American women, whereas Asian women, who consume a traditional diet high in soy products, have a relatively low incidence. Genistein is a prominent iso¯avonoid in soy products and has been proposed as the agent responsible for lowering the rate of breast cancer in Asian women. We investigated the e ects of genistein on cell growth and apoptosis-related gene expression in breast cancer cells MDA-MB-231. We found upregulation of Bax and p21 WAF1 expressions and downregulation of Bcl-2 and p53 expression in genisteintreated cells. Furthermore, DNA ladder formation, CPP32 activation, and PARP cleavage were observed after treatment with genistein, indicating apoptotic cell deaths. Flow cytometry with 7-amino actinomycin D staining showed that the number of apoptotic cells increased with longer treatment of genistein. From these results, we conclude that genistein inhibits the growth of MDA-MB-231 breast cancer cells, regulates the expression of apoptosis-related genes, and induces apoptosis through a p53-independent pathway. The up-regulation of Bax and p21 WAF1 may be the molecular mechanisms by which genistein induces apoptosis, however, further de®nitive studies are needed. These results suggest that genistein may be a potentially e ective chemopreventive or therapeutic agent against breast cancer.

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“…Notably, the internalized anti-CD19 mAb-CD19 complexes showed close physical association with/ attachment to the endosomal membrane [64]. This close association of internalized anti-CD19 mAb with the endosomal membrane likely facilitates the endosomal leakage and/or escape of chemical or biological substances attached to them into the cytosol and provides a cogent explanation for the documented potency of toxin conjugates [65], drug conjugates [66], as well as antisense oligonucleotide conjugates [67] of anti-CD19 mAb against CD19+ leukemia/lymphoma cells. Therefore, we propose that siRNA nanoparticles decorated with a CD19-specific biotargeting moiety would exhibit a significantly improved selective anti-cancer potency against CD19+ B-lineage leukemias and lymphomas.…”

Section: Multifunctional Targeted Sirna Nanoparticles Against Leukemimentioning

confidence: 95%

Nanoscale Small Interfering RNA Delivery Systems For Personalized Cancer Therapy

Uçkun

S²

2012

IJNST

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Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases

Cited by 258 publications

References 55 publications

Thrombin Stimulates Phosphorylation of Insulin-like Growth Factor-1 Receptor, Insulin Receptor Substrate-1, and Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells

Thrombin Stimulates Phosphorylation of Insulin-like Growth Factor-1 Receptor, Insulin Receptor Substrate-1, and Phospholipase C-γ1 in Rat Aortic Smooth Muscle Cells

Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein

Nanoscale Small Interfering RNA Delivery Systems For Personalized Cancer Therapy

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