Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents

Abstract

The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In this study, we found that in APL patients receiving ATRA or As 2 O 3 treatment, the improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding symptoms. Notably, clinical improvement was also correlated to ATRA/As 2 O 3 -induced rapid decrease of membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within NB4 cells were rapidly down-regulated by 1 M ATRA or As 2 O 3 , while 0.2 g/ml DNR increased these TF parameters prior to its effect upon apoptosis induction. The down-regulation of TF mRNA by ATRA was partially de novo protein synthesis-dependent and at least partially attributed to a mechanism of destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA, As 2 O 3 could also induce an accelerated TF protein turnover. These distinct effects were corroborated with the properties of these agents in causing the degradation of PML-RAR␣ protein. All three therapeutic agents, however, enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in endothelium. Taken together, our data suggest that the rapid and distinct regulation of TF on APL cells by these therapeutic agents might at least partially contribute to their effects on APL coagulopathy.

Arsenic trioxide (As2O3) gradually downregulates tissue factor expression without affecting thrombomodulin expression in acute promyelocytic leukemia cells

“…Since the mechanism of action of As 2 O 3 does not involve its binding to retinoic acid receptors (RARs), in contrast to that of retinoic acids (RAs), 4 we have examined the regulation of TM and TF expression in APL cell line, NB4 cells treated with As 2 O 3 alone or in combination with ATRA. Our data generally support a very recent report by Zhu et al, 5 which has appeared in this journal.…”

“…In cells treated with As 2 O 3 , the level of expression of TF mRNA decreased more gradually than that observed in cells treated with ATRA (Figure 3a), 3 tive of coagulopathy and hyperfibrinolysis fibrinogen/fibrin degradation products (FDP) and D-dimers gradually decreased and thus clinical improvement of DIC was also observed. 1,5 Whereas APL patients treated with ATRA show rapid improvement of coagulopathy within a few days, DIC in patients treated with As 2 O 3 improves in 1 week or more (personal communication by Dr Zhou Jin, First College of Harbin Medical University, Harbin, People's Republic of China). The effect of As 2 O 3 in inducing modest TF downregulation without TM upregulation, as shown in this study, seems to be compatible with the gradual and slow improvement of DIC in patients treated with As 2 O 3 .…”

“…Leukemic cells from fresh bone marrow or blood samples were assessed for their in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA) against a panel of drugs used in the current Nordic protocols for AML 2 and ALL, 5 respectively. The FMCA is a non-clonogenic assay, very similar to the more widely used MTT assay, 6 and is based on the measurement of fluorescence generated from hydrolysis of fluorescein diacetate to fluorescein by cells with intact plasma membranes.…”

All-trans retinoic acid/As 2 O 3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia

“…It is well known that the low platelet level in APL results from repression of the normal hematopoiesis and increased consumption͞destruction level because of the coagulopathy. It is thus likely that combination therapy relieves the repression of hematopoiesis more significantly than mono-therapy (5,43). Third, the side effects of combination therapy could be well controlled.…”

Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage

“…4,8 The As 2 O 3 was proved efficient in relapsed APL in many clinical studies, [4][5][6][7][8]13 being able to achieve a high CR rate and alleviate the abnormal coagulopathy. 14,15 In vitro study demonstrated that As 2 O 3 exerted dual effects on APL cells: with induction of apoptosis at higher concentration (1-2 mol/l) and partial differentiation at lower concentrations (0.1-0.5 mol/l). 9,16,22 The mechanism involved in inducing apoptosis has been clarified, 8,[17][18][19][20][21] but that of the differentiation effect is not well known.…”