Induction of macrophage procoagulant expression by cisplatin, daunorubicin and doxorubicin

Abstract

Cisplatin, doxorubicin and daunorubicin (drugs which intercalate with DNA) influenced the membrane-bound procoagulant potential of murine thioglycollate-induced peritoneal exudate (TG-PEC) macrophages and the monocytoid cell line WEHI 265, whereas the antimetabolites 5-fluorouracil and methotrexate had no effect. Enhanced procoagulant was not caused by non-specific toxicity of these agents. Cisplatin directly increased the procoagulant expressed on WEHI 265 cells, whereas MPCA on TG-PEC was enhanced only when cisplatin was combined with a second stimulant, either bacterial lipopolysaccharide (LPS) or interferon (IFN gamma). WEHI 265 cells failed to respond to the anthracycline drugs, either alone or in combination with LPS, whereas they enhanced the IFN gamma response. Doxorubicin and daunorubicin increased the LPS response of TG-PEC by approximately 4-fold and the IFN gamma response by approximately 10-fold. Pulsing experiments suggested that the anthracyclines enhanced procoagulant expression by a mechanism different from cisplatin. Daunorubicin primed TG-PEC within 4 hr to respond to low levels of LPS, whereas either LPS or cisplatin primed these cells to respond to cisplatin or LPS respectively. Furthermore, the procoagulant expressed by TG-PEC stimulated by LPS/cisplatin had properties of tissue factor (TF: 50% total activity) and Factor VIIa (50% total procoagulant)-like activities, whereas the predominant procoagulant on LPS/anthracycline activated TG-PEC was TF-like (70% total activity) with weak Factor VIIa and prothrombinase-like properties.

Identification of Small Molecules with Type I Interferon Inducing Properties by High-Throughput Screening

“…By searching the literature for studies on compounds structurally similar to C3 we discovered that it was previously identified in a HTS as an antibacterial agent [47] and later suggested to be a mitochondrial type II topoisomerase inhibitor with the ability to unwind DNA [48]. The DNA binding activity of C3 would suggest a similar mechanism of action for its IFN induction to that proposed for other FDA approved topoisomerase inhibitors such as doxorubicin, which involves recognition of the compound induced DNA stress and IRF3 nuclear translocation [49], [50]. More investigation will be required to determine whether this is the case.…”

Topoisomerase II Inhibitors Induce DNA Damage-Dependent Interferon Responses Circumventing Ebola Virus Immune Evasion

“…However, no small-molecule inhibitor of VP35 IFN-antagonist function has been described. We assessed the FDA-approved chemotherapeutic drug doxorubicin, which has been reported to induce an IFN response and to stimulate IFN regulatory factor 3 (IRF-3) phosphorylation by an incompletely defined mechanism (38, 39). Doxorubicin activated the IFN-β promoter in the presence or absence of VP35 (Fig.…”

Current understanding of interactions between nanoparticles and the immune system

“…Cytotoxic DNA-intercalating drugs used to treat cancer (e.g. doxorubicin, daunorubicin, and vincristine) are known to induce PCA and DIC (Wheeler and Geczy, 1990; Swystun et al, 2009; Kim et al, 2011). Formulating these drugs using nanotechnology carriers may help avoiding the toxicity.…”