(2,6-Dimethylphenyl)arsonic Acid Induces Apoptosis through the Mitochondrial Pathway, Downregulates XIAP, and Overcomes Multidrug Resistance to Cytostatic Drugs in Leukemia and Lymphoma Cells In Vitro.

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.

Synthesis, characterization, and biomedical evaluation of ethylene-bridged tetra-NHC Pd(ii), Pt(ii) and Au(iii) complexes, with apoptosis-inducing properties in cisplatin-resistant neuroblastoma cells.

Synthesis and characterization of the first two cyclic ethylene-bridged tetradentate NHC ligands, with an unsaturated (imidazole) and saturated backbone (2-imidazoline), are described. Complexes of both ligands containing palladium(ii) have been obtained. For platinum(ii) and gold(iii), only the unsaturated tetracarbene complexes could be isolated. The attempts to synthesize a methylene-bridged 2-imidazoline macrocycle are also described. Furthermore, a novel bisimidazolinium ligand precursor and its open-chain PdII and PtII tetracarbene complexes are obtained. Finally, it is shown that the unsaturated gold(iii) tetracarbene is able to induce apoptosis in malignant SK-N-AS neuroblastoma cells via the mitochondrial and ROS pathway and overcomes resistance to cisplatin in vitro.

Novel gold(I) complexes induce apoptosis in leukemia cells via the ROS-induced mitochondrial pathway with an upregulation of Harakiri and overcome multi drug resistances in leukemia and lymphoma cells and sensitize drug resistant tumor cells to apoptosis in vitro.

Gold complexes could be promising for tumor therapy because of their cytotoxic and cytostatic properties. We present novel gold(I) complexes and clarify whether they also show antitumor activity by studying apoptosis induction in different tumor cell lines in vitro, comparing the compounds on resistant cells and analyzing the mechanism of action. We particularly highlight one gold complex that shows cytostatic and cytotoxic effects on leukemia and lymphoma cells already in the nanomolar range, induces apoptosis via the intrinsic signaling pathway, and plays a role in the production of reactive oxygen species. Furthermore, not only did we demonstrate a large number of resistance overcomes on resistant cell lines, but some of these cell lines were significantly more sensitive to the new gold compound. Our results show promising properties for the gold compound as anti-tumor drug and suggest that it can subvert resistance mechanisms and thus targets resistant cells for killing.

Ruthenium Complex HB324 Induces Apoptosis via Mitochondrial Pathway with an Upregulation of Harakiri and Overcomes Cisplatin Resistance in Neuroblastoma Cells In Vitro.

Ruthenium(II) complexes with N-heterocyclic carbene (NHC) ligands have recently attracted attention as novel chemotherapeutic agents. The complex HB324 was intensively studied as an apoptosis-inducing compound in resistant cell lines. HB324 induced apoptosis via mitochondrial pathways. Of particular interest is the upregulation of the Harakiri resistance protein, which inhibits the anti-apoptotic and death repressor proteins Bcl-2 (B-cell lymphoma 2) and BCL-xL (B-cell lymphoma-extra large). Moreover, HB324 showed synergistic activity with various established anticancer drugs and overcame resistance in several cell lines, such as neuroblastoma cells. In conclusion, HB324 showed promising potential as a novel anticancer agent in vitro, suggesting further investigations on this and other preclinical ruthenium drug candidates.

The gallium complex KP46 sensitizes resistant leukemia cells and overcomes Bcl-2-induced multidrug resistance in lymphoma cells via upregulation of Harakiri and downregulation of XIAP in vitro.

Tris-(8-quinolinolato)gallium(III) (KP46, AP-002) is an orally administered investigational anticancer and bone-protective drug currently being evaluated in patients with advanced solid tumors with bone involvement. Despite the clinical efficacy of other gallium compounds in non-Hodgkin's lymphoma, effects of KP46 in hematological tumor settings have not been studied systematically before. We report here intriguing activities in various human cell lines, including such with multidrug resistance (MDR): In Nalm-6 lymphoblastic leukemia cell sublines, KP46 was capable of overcoming P-gp-related as well as P-gp-unrelated MDR. Apoptosis induction by KP46 was unaffected by bcl2-mediated vincristine-induced MDR in a BJAB lymphoma cell subline and even enhanced in a K562 leukemia subline with daunorubicin-induced MDR, which could be re-sensitized to daunorubicin by KP46. As the latter resistance is associated with lowered Harakiri (HRK) protein levels, a modulating effect of KP46 on HRK expression is suggested. This is consistent with the significant high upregulation of HRK on RNA and protein levels observed in KP46-treated parental BJAB cells according to qPCR and Western blot analysis, respectively. Furthermore, KP46 significantly reduces the protein level of X-linked inhibitor of apoptosis (XIAP) in BJAB cells, the most potent known inhibitor of apoptosis. Overall, these results indicate both a higher potential of HRK and XIAP as cellular targets for cancer therapy and a broader therapeutic potential of KP46 than hitherto envisaged.

An organometallic analogue of combretastatin A-4 and its apoptosis-inducing effects on lymphoma, leukemia and other tumor cells in vitro.

Hexacarbonyl[1,3-dimethoxy-5-((4'-methoxyphenyl)ethynyl)benzene]dicobalt (NAHO27), an organometallic analogue of combretastatin A-4, has been synthesized and its activity against lymphoma, leukemia, breast cancer and melanoma cells has been investigated. It was shown that NAHO27 specifically induces apoptosis in BJAB lymphoma and Nalm-6 leukemia cells at low micromolar concentration and does not affect normal leukocytes in vitro. It also proved to be active against vincristine and daunorubicin resistant leukemia cell lines with p-glycoprotein-caused multidrug resistance and showed a pronounced (550%) synergistic effect when co-applied with vincristine at very low concentrations. Mechanistic investigations revealed NAHO27 to induce apoptosis via the mitochondrial (intrinsic) pathway as reflected by the processing of caspases 3 and 9, the involvement of Bcl-2 and smac/DIABLO, and the reduction of mitochondrial membrane potential. Gene expression analysis and protein expression analysis via western blot showed an upregulation of the proapoptotic protein harakiri by 9%.

Dihydroxyquingdainone Induces Apoptosis in Leukaemia and Lymphoma Cells via the Mitochondrial Pathway in a Bcl-2- and Caspase-3-Dependent Manner and Overcomes Resistance to Cytostatic Drugs In Vitro.

Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted α-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 µmole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6/BeKa) with p-glycoprotein expression.

Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype-phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype-phenotype correlations encouraging further analyses.

B-nor-methylene Colchicinoid PT-100 Selectively Induces Apoptosis in Multidrug-Resistant Human Cancer Cells via an Intrinsic Pathway in a Caspase-Independent Manner.

Colchicine, the main active alkaloid from Colchicum autumnale L., is a potent tubulin binder and represents an interesting lead structure for the development of potential anticancer chemotherapeutics. We report on the synthesis and investigation of potentially reactive colchicinoids and their surprising biological activities. In particular, the previously undescribed colchicinoid PT-100, a B-ring contracted 6-exo-methylene colchicinoid, exhibits extraordinarily high antiproliferative and apoptosis-inducing effects on various types of cancer cell lines like acute lymphoblastic leukemia (Nalm6), acute myeloid leukemia (HL-60), Burkitt-like lymphoma (BJAB), human melanoma (MelHO), and human breast adenocarcinoma (MCF7) cells at low nanomolar concentrations. Apoptosis induction proved to be especially high in multidrug-resistant Nalm6-derived cancer cell lines, while healthy human leukocytes and hepatocytes were not affected by the concentration range studied. Furthermore, caspase-independent initiation of apoptosis via an intrinsic pathway was observed. PT-100 also shows strong synergistic effects in combination with vincristine on BJAB and Nalm6 cells. Cocrystallization of PT-100 with tubulin dimers revealed its (noncovalent) binding to the colchicine-binding site of ß-tubulin at the interface to the α-subunit. A pronounced effect of PT-100 on the cytoskeleton morphology was shown by fluorescence microscopy. While the reactivity of PT-100 as a weak Michael acceptor toward thiols was chemically proven, it remains unclear whether this contributes to the remarkable biological properties of this unusual colchicinoid.

KP772 overcomes multiple drug resistance in malignant lymphoma and leukemia cells in vitro by inducing Bcl-2-independent apoptosis and upregulation of Harakiri.

Despite high cure rates in pediatric patients with acute leukemia, development of resistance limits the efficacy of antileukemic therapy. Tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) (KP772) is an experimental antineoplastic agent to which multidrug-resistant cell models have shown hypersensitivity. Antiproliferative and apoptotic activities of KP772 were tested in leukemia, lymphoma and solid tumor cell lines as well as primary leukemia cells (isolated from the bone marrow of a child with acute myeloid leukemia (AML). The ability to overcome drug resistances was investigated in doxorubicin- and vincristine-resistant cell lines. Real-time PCR was used to gain insight into the mechanism of apoptosis induction. KP772 inhibited proliferation and induced apoptosis in various leukemia and lymphoma cell lines in a concentration-dependent manner (LC50 = 1-2.5 µM). Primary AML cells were also sensitive to KP772, whereas daunorubicin showed no significant effect. KP772 induces apoptosis independently of Bcl-2, Smac, and the CD95 receptor and is also effective in caspase 3-deficient MCF7 cells, indicating that apoptosis is partly triggered independently of caspase 3. mRNA expression profiling revealed an upregulation of the BH3-only Bcl-2 protein Harakiri in the course of KP772-induced apoptosis. Remarkably, KP772 overcame drug resistance to doxorubicin and vincristine in vitro, and the apoptotic effect in resistant cells was even superior to that in non-resistant parental cells. In combination with vincristine, doxorubicin and cytarabine, synergistic effects were observed in BJAB cells. The cytotoxic potency in vitro/ex vivo and the remarkable ability to overcome multidrug resistance propose KP772 as a promising candidate drug for antileukemic therapy, especially of drug-refractory malignancies.Graphic abstract.

Gold(I) Bis(1,2,3-triazol-5-ylidene) Complexes as Promising Selective Anticancer Compounds.

The synthesis and antiproliferative activity of Mes- and iPr-substituted gold(I) bis(1,2,3-triazol-5-ylidene) complexes in various cancer cell lines are reported, showing nanomolar IC50 values of 50 nM (lymphoma cells) and 500 nM (leukemia cells), respectively (Mes < iPr). The compounds exclusively induce apoptosis (50 nM to 5 µM) instead of necrosis in common malignant blood cells (leukemia cells) and do not affect non-malignant leucocytes. Remarkably, the complexes not only overcome resistances against the well-established cytostatic etoposide, cytarabine, daunorubicin, and cisplatin but also promote a synergistic effect of up to 182% when used with daunorubicin. The present results demonstrate that gold(I) bis(1,2,3-triazol-5-ylidene) complexes are highly promising and easily modifiable anticancer metallodrugs.

A metal-free salalen ligand with anti-tumor and synergistic activity in resistant leukemia and solid tumor cells via mitochondrial pathway.

PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.

Sensitizing multidrug-resistant leukemia cells to common cytostatics by an aluminium-salen complex that has high-apoptotic effects in leukemia, lymphoma and mamma carcinoma cells.

We investigated the aluminium-salen complex MBR-8 as a potential anti-cancer agent. To see apoptotic effects induced by MBR-8, alone and in combination with common cytostatic drugs, DNA-fragmentations were studied using the flow cytometric analysis. Western blot analysis and measurement of the mitochondrial membrane potential with a JC-1 dye were employed to identify the pathway of apoptosis. An impressive overcoming of multidrug-resistance in leukemia (Nalm6) cells was observed. Additionally, solid tumor cells including Burkitt-like lymphoma (BJAB) and mamma carcinoma cells (MCF-7) are affected by MBR-8 in the same way. Western blot analysis revealed activation of caspase-3. MBR-8 showed very pronounced selectivity with regard to tumor cells and high synergistic effects in Nalm6 and daunorubicin-resistant Nalm6 cells when administered in combination with vincristine, daunorubicin and doxorubicin. The aluminium-salen complex MBR-8 showed very promising anti-cancer properties which warrant further development towards a cytostatic agent for future chemotherapy. Studies on aluminium compounds for cancer therapy are rare, and our report adds to this important body of knowledge.

Severe adverse events during sirolimus "off-label" therapy for vascular anomalies.

OBJECTIVES: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. METHODS: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. RESULTS: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis. CONCLUSIONS: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Discovery of a cobalt (III) salen complex that induces apoptosis in Burkitt like lymphoma and leukemia cells, overcoming multidrug resistance in vitro.

A very small number of cobalt complexes is examined in oncology research. In this work, we investigate the cobalt (III) salen complex MBR-60 that turns out to be a promising anticancer drug. It induces apoptosis in Nalm6 leukemia and BJAB lymphoma cells and overcomes multidrug resistances by blocking the drug efflux pump P-glycoprotein. It further develops the apoptotic effects over the intrinsic pathway. An activation of caspase-3, caspase-8 and caspase-9 can be detected by western blot analysis. The independence of CD95 is shown by similar apoptotic inductions in BJAB and BJAB FADDdn cells. MBR-60 displays synergistic effects with daunorubicin and vincristine and has a selectivity to tumor cells. In comparison to the apoptotic effects of MBR-60 in BJAB lymphoma cells, the cobalt-free ligand 5 does not influence these cells. The research highlights that a cobalt complex has a therapeutic potential for cancer treating with a focus on drug-resistant tumors.

Organoarsenic Compounds with In Vitro Activity against the Malaria Parasite Plasmodium falciparum.

The rapid development of parasite drug resistance as well as the lack of medications targeting both the asexual and the sexual blood stages of the malaria parasite necessitate the search for novel antimalarial compounds. Eleven organoarsenic compounds were synthesized and tested for their effect on the asexual blood stages and sexual transmission stages of the malaria parasite Plasmodium falciparum using in vitro assays. The inhibitory potential of the compounds on blood stage viability was tested on the chloroquine (CQ)-sensitive 3D7 and the CQ-resistant Dd2 strain using the Malstat assay. The most effective compounds were subsequently investigated for their effect on impairing gametocyte development and gametogenesis, using the gametocyte-producing NF54 strain in respective cell-based assays. Their potential toxicity was investigated on leukemia cell line Nalm-6 and non-infected erythrocytes. Five out of the 11 compounds showed antiplasmodial activities against 3D7, with half-maximal inhibitory concentration (IC50) values ranging between 1.52 and 8.64 µM. Three of the compounds also acted against Dd2, with the most active compound As-8 exhibiting an IC50 of 0.35 µM. The five compounds also showed significant inhibitory effects on the parasite sexual stages at both IC50 and IC90 concentrations with As-8 displaying the best gametocytocidal activity. No hemolytic and cytotoxic effect was observed for any of the compounds. The organoarsenic compound As-8 may represent a good lead for the design of novel organoarsenic drugs with combined antimalarial and transmission blocking activities.

Indoor Wall Climbing with Childhood Cancer Survivors: An Exploratory Study on Feasibility and Benefits.

BACKGROUND: Exercise interventions in pediatric oncology include primarily traditional types of physical activity (PA) such as endurance and strength training, while there is a growing interest in recreational types of PA for pediatric cancer survivors, as well. One of these motivating and fun activities is indoor wall climbing. Therefore, this exploratory study aims to evaluate the feasibility and beneficial effects of a 10-week indoor wall climbing intervention in pediatric oncology. PATIENTS: Thirteen childhood cancer survivors aged 6-21 years were included after cessation of their inpatient medical treatment of whom eleven completed the study. METHODS: Study participants completed measurements of physical functioning at baseline (t0) and post-intervention (t1), as well as a questionnaire on program satisfaction at t1. RESULTS: Survivors participated in 57.43±31.77% of the climbing sessions and no adverse events occurred. Most study participants evaluated the climbing experience to be fun and motivational. One child stated that the climbing intervention was too exhausting/overstraining. Significant positive effects were found in terms of ankle DF-ROM and ankle DF strength. DISCUSSION: Indoor wall climbing seems feasible with childhood cancer survivors and suggests beneficial potentials on physical functioning. However, some preconditions (i. e. close supervision; slow increase of intensity; sufficient breaks) must be ensured. CONCLUSION: Indoor wall climbing could be a motivational adjunct to traditional types of exercise in pediatric oncology.

Sickle cell disease in Germany: Results from a national registry.

BACKGROUND: Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. PROCEDURE: A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. RESULTS: Most patients had homozygous SCD (HbSS 75.1%, HbS/ß-thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6-4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/ß thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. CONCLUSION: With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.

Impact of A Six Week Training Program on Ventilatory Efficiency, Red Blood Cell Rheological Parameters and Red Blood Cell Nitric Oxide Signaling in Young Sickle Cell Anemia Patients: A Pilot Study.

Patients with sickle cell anemia (SCA) show impaired ventilatory efficiency, altered blood rheology, high levels of oxidative/nitrosative stress and enhanced hemolysis with large amounts of circulating free hemoglobin, which reduces nitric oxide (NO) bioavailability. The aim of the study was to investigate whether physical exercise could improve these physiological and biological markers described to contribute to SCA pathophysiology. Twelve SCA patients participated in a controlled six weeks training program with moderate volume (two sessions per week with 15-30 min duration per session) and intensity (70% of the first ventilatory threshold). Parameters were compared before (T0) and after (T1) training. Daily activities were examined by a questionnaire at T0 and one year after the end of T1. Results revealed improved ventilatory efficiency, reduced nitrosative stress, reduced plasma free hemoglobin concentration, increased plasma nitrite levels and altered rheology at T1 while no effect was observed for exercise performance parameters or hematological profile. Red blood cell (RBC) NO parameters indicate increased NO bioavailability which did not affect RBC deformability. Participants increased their daily life activity level. The data from this pilot study concludes that even low intensity activities are feasible and could be beneficial for the health of SCA patients.

Effect of acute exercise on RBC deformability and RBC nitric oxide synthase signalling pathway in young sickle cell anaemia patients.

Sickle cell anaemia (SCA) is characterized by reduced red blood cell (RBC) deformability and nitric oxide (NO) bioavailability. The aim of the study was to investigate whether exercise might affect these parameters in SCA. SCA patients and healthy controls (AA) performed an acute submaximal exercise test until subjects reached the first ventilatory threshold (VT 1). Blood was sampled at rest and at VT 1. At rest, free haemoglobin level was higher and RBC count, haemoglobin and haematocrit were lower in SCA compared to AA. RBC deformability was lower in SCA. Exercise had no effect on the tested parameters. RBC NO level was higher in SCA compared to AA at rest and significantly decreased after exercise in SCA. This might be related to a reduction in RBC-NO synthase (RBC-NOS) activation which was only observed in SCA after exercise. Free radical levels were higher in SCA at rest but concentration was not affected by exercise. Marker for lipid peroxidation and antioxidative capacity were similar in SCA and AA and not affected by exercise. In conclusion, a single acute submaximal bout of exercise has no deleterious effects on RBC deformability or oxidative stress markers in SCA, and seems to modulate RBC-NOS signalling pathway.