Cisplatin Triggers Platelet Activation

Togna, G.; Togna, Anna Rita; Franconi, Matteo; Caprino, L.

doi:10.1016/s0049-3848(00)00294-2

Cited by 127 publications

(76 citation statements)

References 28 publications

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“…In view of these and the above-mentioned findings, it is of interest to note that AA-dependent tumor cell death involves induction of mitochondrial permeability transition (10). Several anticancer therapies, including cisplatin, irradiation, and retinoids, all used in the treatment of neuroblastoma, may induce intracellular release of AA (11,12). Our findings raise the possibility that children with neuroblastoma may benefit from NSAID-mediated inhibition of AA metabolism in combination with therapies that increase the intracellular concentration of AA.…”

Section: Resultsmentioning

confidence: 99%

Cyclooxygenase-2 Is Expressed in Neuroblastoma, and Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis and Inhibit Tumor Growth In vivo

Johnsen

Lindskog²,

Ponthan³

et al. 2004

Cancer Research

104

103

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Neuroblastoma is the single most common and deadly tumor of childhood and is often associated with therapy resistance. Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to prostaglandins. COX-2 is up-regulated in several adult epithelial cancers and is linked to proliferation and resistance to apoptosis. We detected COX-2 expression in neuroblastoma primary tumors and cell lines but not in normal adrenal medullas from children. Treatment of neuroblastoma cells with nonsteroidal anti-inflammatory drugs, inhibitors of COX, induced caspasedependent apoptosis via the intrinsic mitochondrial pathway. Treatment of established neuroblastoma xenografts in nude rats with the dual COX-1/COX-2 inhibitor diclofenac or the COX-2-specific inhibitor celecoxib significantly inhibited tumor growth in vivo (P < 0.001). In vitro, arachidonic acid and diclofenac synergistically induced neuroblastoma cell death. This effect was further pronounced when lipooxygenases were simultaneously inhibited. Proton magnetic resonance spectroscopy ( 1 H MRS) of neuroblastoma cells treated with COX inhibitors demonstrated accumulation of polyunsaturated fatty acids and depletion of choline compounds. Thus, 1 H MRS, which can be performed with clinical magnetic resonance scanners, is likely to provide pharmacodynamic markers of neuroblastoma response to COX inhibition. Taken together, these data suggest the use of nonsteroidal anti-inflammatory drugs as a novel adjuvant therapy for children with neuroblastoma.

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Section: Resultsmentioning

confidence: 99%

Cyclooxygenase-2 Is Expressed in Neuroblastoma, and Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis and Inhibit Tumor Growth In vivo

Johnsen

Lindskog²,

Ponthan³

et al. 2004

Cancer Research

104

103

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“…Together, our findings may have clinical implications in the use of COX inhibitors during cisplatin chemotherapy and provide mechanistic insight required to improve treatment effectiveness 35 and alleviate some of its complications. 36 Materials and Methods Reagents. Anti-GST polyclonal anti-body (cat.…”

Section: Discussionmentioning

confidence: 99%

Thromboxane A2 modulates cisplatin-induced apoptosis through a Siva1-dependent mechanism

Iorio-Morin

Germain

et al. 2012

Cell Death Differ

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Thromboxane A 2 (TXA 2 ) is an important lipid mediator whose function in apoptosis is the subject of conflicting reports. Here, a yeast two-hybrid screen for proteins that interact with the C-terminus of the TXA 2 receptor (TP) identified Siva1 as a new TP-interacting protein. Contradictory evidence suggests pro-and anti-apoptotic roles for Siva1. We show that a cisplatin treatment induces TXA 2 synthesis in HeLa cells. We demonstrate that endogenous TP stimulation promotes cisplatin-induced apoptosis of HeLa cells and that such modulation requires the expression of Siva1, as evidenced by inhibiting its endogenous expression using siRNAs. We reveal that, upon stimulation of TP, degradation of Siva1 is impeded, resulting in an accumulation of the protein, which translocates from the nucleus to the cytosol. Translocation of Siva1 correlates with its reduced interaction with Mdm2 (an inhibitor of p53 signalling), as well as with its increased interaction with TRAF2 and XIAP (known to enhance pro-apoptotic signalling). Our data provide a model that reconciles the pro-and anti-apoptotic roles that were reported for Siva1 and identify a new mechanism for promoting apoptosis by G protein-coupled receptors. Our findings may have implications in the use of cyclo-oxygenase inhibitors during cisplatin chemotherapy and might provide a target to reduce cisplatin toxicity on non-cancerous tissues.

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“…The mechanisms by which cisplatin induces thrombosis is not well known but in vitro studies suggest increase in the level of TF (48), platelet activation (50) and increased levels of von Willebrand factor suggesting endothelial injury (58). The latter perhaps explain the cisplatin induced arterial thrombosis.…”

Section: Cisplatin Based Regimensmentioning

confidence: 99%