Curcumin and its analogue induce apoptosis in leukemia cells and have additive effects with bortezomib in cellular and xenograft models.

Combination therapy of bortezomib with other chemotherapeutics is an emerging treatment strategy. Since both curcumin and bortezomib inhibit NF-κB, we tested the effects of their combination on leukemia cells. To improve potency, a novel Mannich-type curcumin derivative, C-150, was synthesized. Curcumin and its analogue showed potent antiproliferative and apoptotic effects on the human leukemia cell line, HL60, with different potency but similar additive properties with bortezomib. Additive antiproliferative effects were correlated well with LPS-induced NF-κB inhibition results. Gene expression data on cell cycle and apoptosis related genes, obtained by high-throughput QPCR, showed that curcumin and its analogue act through similar signaling pathways. In correlation with in vitro results similar additive effect could be obsereved in SCID mice inoculated systemically with HL60 cells. C-150 in a liposomal formulation given intravenously in combination with bortezomib was more efficient than either of the drugs alone. As our novel curcumin analogue exerted anticancer effects in leukemic cells at submicromolar concentration in vitro and at 3 mg/kg dose in vivo, which was potentiated by bortezomib, it holds a great promise as a future therapeutic agent in the treatment of leukemia alone or in combination.

Simultaneous engagement of thrombin and Fc gamma RIIA receptors results in platelets expressing high levels of procoagulant proteins.

Collagen and thrombin-activated (COAT) platelets represent a unique subset of activated platelets that exhibit high levels of several adhesive and procoagulant alpha-granule proteins on their surface. In this report we demonstrate that a similar subpopulation of platelets can also be generated by the combined stimulation of Fc gamma RIIA and thrombin receptors. Platelets activated in this manner are referred to as Fc receptor and thrombin-activated (FcRT) platelets, and they share many of the characteristics of the formerly observed COAT platelets, including aminophospholipid exposure, adhesive and procoagulant protein enrichment, increased frequency among young platelets, and sensitivity to transglutaminase inhibitors. Although Fc gamma RIIA receptor activation can be achieved either with anti-CD9 monoclonal antibodies (ALB-6 and ML-13) or with direct Fc receptor cross-linking, FcRT platelet generation occurs only with concurrent or slightly delayed thrombin stimulation. In fact, when thrombin was the second agonist, time delays of up to 120 seconds after Fc gamma RIIA receptor stimulation had little effect on the generation of FcRT platelets; however, a similar delay for convulxin plus thrombin activation results in a 90% diminution in COAT platelet production. FcRT platelet formation in platelet-poor plasma and whole blood was also investigated, and results were similar to those observed with gel-filtered platelets. Previous experiments with COAT platelet formation used physiologic agonists (collagen and thrombin) that might be encountered under either physiologic or pathologic conditions; however, the current experiments with Fc receptor stimulation offer the first example in which these highly prohemostatic platelets are likely to be strictly pathogenic.

[Hairy cell leukemia: authors' own experience (1977-1998)]. / A "hajas" sejtes leukaemiáról: saját tapasztalatok (1977-1998).

Hairy cell leukaemia (HCL) is a rare, clinically and haematologically well characterised entity. The prognosis of patients with hairy cell leukaemia has significantly improved due to the new therapeutic approaches. Development of diagnostic and therapeutic methods, together with the analysis of their own hairy cell leukaemia patients, is reviewed by the authors. Between 1977 and 1998 twenty five patients (16 male, 9 female) were treated. The malignant cells were usually analysed by morphological and cytochemical methods and recently flow cytometric analysis could be performed in eight patients. Splenectomy with lethal outcome in six patients was performed in 21 cases. Approximately one third of patients received interferon, while 2-chlorodeoxyadenosine was given only to three patients. Favourable experiences obtained by splenectomy and efficacy of interferon treatment are emphasised, but according to the literature and their own results administration of purine analogues can be highly recommended in the future.

Increased platelet activation and decreased fibrinolysis in the pathogenesis of aseptic necrosis of the femoral head.

Thrombotic events, increased tendency toward intravascular thrombosis and decreased fibrinolysis seem to be possible pathologic causes for aseptic necrosis of the femoral head (ANFH) in adults. This project was to study whether either increased platelet activation or decreased fibrinolytic activity and/or any other thrombogenic factor may be implicated in the evolvement of ANFH. The speed of the in vitro lysis was significantly lower in patients (both in primary and in secondary cases) compared with healthy controls. The platelet activation (measuring with beta TG) proved to be significantly higher in the primary group as well as in the secondary group compared with healthy controls. Lp(a) levels were elevated in primary and secondary cases. This alteration was more characteristic in the primary cases. Fibrinogen levels were also elevated in the primary group, but the difference was not significant. The data shown here may further support that hypofibrinolysis and increased thrombogenesis are major causes of ANFH. Early diagnosis of ANFH increases the chances of modifying the course of this disabling disease.