thromboplastin and tamibarotene

Idarubicin (IDR), cytarabine (AraC), and tamibarotene (Am80) are effective for treatment of acute myeloid leukemia (AML). In acute leukemia, the incidence of venous thromboembolism or disseminated intravascular coagulation is associated with induction chemotherapy. Procoagulant effects of IDR, AraC, and Am80 were investigated in a vascular endothelial cell line EAhy926 and AML cell lines HL60 (AML M2), NB4 (AML M3, APL), and U937 (AML M5), focusing on tissue factor (TF), phosphatidylserine (PS), and thrombomodulin (TM). IDR induced procoagulant activity on the surface of vascular endothelial and AML cell lines. Expression of TF antigen, TM antigen, and PS were induced by IDR on the surface of each cell line, whereas expression of TF and TM mRNAs were unchanged. Conversely, Am80 decreased TF exposure and procoagulant activity, and increased TM exposure on NB4 cells. In NB4 cells, we observed downregulation of TF mRNA and upregulation of TM mRNA. These data suggest IDR may induce procoagulant activity in vessels by apoptosis through PS exposure and/or TF expression on vascular endothelial and AML cell lines. Am80 may suppress blood coagulation through downregulation of TF expression and induction of TM expression. Our methods could be useful to investigate changes in procoagulant activity induced by antineoplastic drugs.

Topics: Antineoplastic Agents; Benzoates; Cell Line, Tumor; Cytarabine; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Idarubicin; Leukemia, Myeloid, Acute; Phosphatidylserines; Tetrahydronaphthalenes; Thrombomodulin; Thromboplastin

Retinoids are involved in cell differentiation, morphogenesis, proliferation and antineoplasic processes. Thus, the retonoic acid receptor (RARalpha) agonist, AM80, regulates tissue factor (TF), thrombomodulin (TM) expression and granulocytic differentiation in promyelocytic cells, while the RARgamma-selective retinoid, CD437, inhibits in vitro cell proliferation and induces apoptosis. The mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K) pathways constitute key integration points along the signal transduction cascades that link diverse extracellular stimuli to proliferation, differentiation and survival.. PI3K and MEK/ERK kinase-dependent pathways were examined as potential targets of retinoid signaling. Likewise, by using specific inhibitors, the role of those kinases in retinoid-induced granulocytic differentiation, apoptosis, and TF and TM expression n NB4 cells were analyzed.. AM80-treated NB4 cells had increased PI3K activity and phosphoinositide turnover. High steady-state pERK-1/-2 activity levels were not significantly changed by AM80. Yet, PI3K inhibitor LY294002 significantly reduced AM80-elicted ERK-1/-2 activity. Thus, the PI3K pathway might contribute to elevated ERK-1/-2 activity in NB4 cells. Inhibition of the PI3K and MEK/ERK pathways reversed AM80-induced granulocytic differentiation, TF down-regulation and TM induction. Besides, CD437 significantly reduced ERK-1/-2 activity of NB4 cells. Further ERK-1/-2 activity inhibition with the MEK inhibitor, PD98059, increased the retinoid pro-apoptotic effect with an additive effect.. Regardless the different regulation of PI3K and MAPK pathways promoted by AM80 and CD437, there is a varying degree of cross-talk between these pathways in the control of the overall response of promyelocytic cells to retinoids. Thus, disruption of targeted pathways, together with specific retinoids, might be an effective therapeutic treatment for acute promyelocytic leukemia.

Topics: Apoptosis; Benzoates; Cell Differentiation; Cell Line, Tumor; Flavonoids; Gene Expression; Humans; Leukemia, Promyelocytic, Acute; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Retinoids; Tetrahydronaphthalenes; Thrombomodulin; Thromboplastin