Paclitaxel downregulates tissue factor in cancer and host tumour-associated cells.
Paclitaxel, a microtubule-stabilising compound with potent anti-tumour activity, has been clinically used in a wide variety of malignancies. Tissue factor (TF) is often expressed by tumour-associated endothelial and inflammatory cells, as well as by cancer cells themselves, and it is considered a hallmark of cancer progression. We investigated whether paclitaxel could modulate TF in human mononuclear (MN) cells, human umbilical vein endothelial cells (HUVEC) and the metastatic breast carcinoma cell line MDA-MB-231. Cells were incubated with or without paclitaxel at 37 degrees C. At the end of incubation, cells were disrupted and tested for procoagulant activity by a one-stage clotting assay, for TF antigen levels by ELISA and TF mRNA by real-time RT-PCR. IL-6 and IL-1beta were tested by ELISA in conditioned medium. Both the strong TF activity and antigen constitutively expressed by MDA-MB-231 and the TF induced by LPS, TNF-alpha and IL-1beta in MN cells and HUVEC were significantly reduced by paclitaxel. In the presence of paclitaxel, lower TF mRNA levels were also detected. Since paclitaxel has been shown to induce the expression of inflammatory genes in monocytes and tumour cells, we tested whether paclitaxel could influence IL-6 and IL-1beta release from the cells used in this paper. Neither the constitutive expression of IL-6 and IL-1beta by MDA-MB-231 nor the basal and LPS-induced release from MN cells and HUVEC was affected. Our data support the hypothesis that the anti-tumour effects of paclitaxel may, at least in part, be mediated by the capacity of this drug to modulate the procoagulant potential of cancer and host cells.
Napoleone
Emanuela
E
Laboratory of Thrombosis and Cancer Research, Research Laboratories, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Largo Gemelli, 1, 86100 Campobasso, CB, Italy.
Zurlo
Filomena
F
Latella
Maria Carmela
MC
Amore
Concetta
C
Di Santo
Angelomaria
A
Iacoviello
Licia
L
Donati
Maria Benedetta
MB
Lorenzet
Roberto
R
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D013925:Thromboplastin / Q000187:drug effects / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D053583:Interleukin-1beta; D015850:Interleukin-6; C053675:endothelial cell procoagulant activity; D013925:Thromboplastin; D017239:Paclitaxel