New, asymmetric quinizarin-Au(I)-NHC complexes were designed, isolated, and fully characterised including by single crystal X-ray crystallography. Cytotoxicity studies showed effective growth inhibition in HeLa cervical cancer cells with IC50 values ranging from 2.4 μM to 5.3 μM. The successful cellular uptake was evidenced by X-ray fluorescence imaging on cryo-preserved whole HeLa cells and the sub-cellular localisation was monitored by live-cell fluorescence microscopy. Notably, complex 2 b showed circumvention of acquired anthracycline resistance in K562 leukaemia cells as well as synergistic activity with doxorubicin against both wild-type and anthracycline-resistant Nalm-6 leukaemia cells. Interestingly, sub-cellular localisation towards mitochondria proved to be more important than the compounds' overall cytotoxicity for potent antiproliferative activity and to achieve effective resistance circumvention.

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.

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.

From previous studies, it is evident that metal-organic gold(I) complexes have antiproliferative activities. The aim of this study is not only to find new anticancer agents but also to overcome existing cytostatic resistance in cancer cells. The synthesis and medicinal evaluation of two cationic 1,3-disubstituted gold(I) bis-tetrazolylidene complexes 1 and 2 are reported. To determine apoptosis-inducing properties of the complexes, DNA fragmentation was measured using propidium iodide staining followed by flow cytometry. Gold(I) complex 1 targets explicitly malignant cells, effectively inhibiting their growth and selectively inducing apoptosis without signs of necrosis. Even in cells resistant to common treatments such as doxorubicin, it overcomes multidrug resistance and sensitizes existing drug-resistant cells to common cytostatic drugs. It is assumed that gold(I) complex 1 involves the mitochondrial pathway in apoptosis and targets members of the BCL-2 family, enhancing its potential as a therapeutic agent in cancer treatment.

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.

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.

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.

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 β-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.

Whole-body vibration (WBV) is a feasible and potentially beneficial exercise strategy for managing neuromuscular impairments like decreased strength or flexibility, mobility limitations and bone health in pediatric cancer survivors. However, as starting rehabilitation as early as possible is recommended to preserve physical function, this study investigated the feasibility of WBV for patients receiving cancer treatment for first cancer diagnosis. Eleven patients (various types of cancer, ages 7–17) participated in the supervised WBV intervention concomitant to acute cancer treatment, which involved chemotherapy. Training was implemented as part of a general exercise program and offered 3 days per week during hospitalization (warm-up, four progressive training exercises comprising 60–120 s, 21–27 Hz, 2 mm peak-to-peak-displacement). Feasibility, which was defined as the absence of WBV-related serious adverse events leading to study dropout, was primarily evaluated. Training documentation was additionally analyzed. As a main result, no serious adverse events leading to study dropout were reported. However, two incidents of bleeding (adverse events) were observed in patients with bleeding tendencies and low platelets (thrombocytes < 30,000/μL). After adjusting the platelet count threshold for WBV participation to 30,000/μL, no further incidents occurred. Moreover, due to WBV-related side effects like physical exhaustion, 11% of all training sessions had to be stopped and another 11% required reductions in the vibration load. Patients participated in 48% of the planned sessions. While main reasons for non-attendance were medical issues (35%), only few WBV sessions were missed, not completed or needed modifications due to motivational issues. Consequently, WBV seems to be feasible for inpatient pediatric patients receiving chemotherapy for first cancer diagnosis, given a sufficiently high platelet count of at least 30,000/μL. Although WBV tolerance and training motivation appear high, patient’s reduced medical condition during hospitalization can negatively impact training progression and attendance. Future research is required to confirm our findings on feasibility and to assess efficiency of WBV training for pediatric cancer patients receiving cancer treatment.

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.

Zusammenfassung Bei einem Sensomotoriktraining (SMT), hier konkret einem Gleichgewichtstraining als Unterform des SMT, werden Übungen auf unterschiedlich stabilen Untergründen und in verschiedenen Standpositionen durchgeführt. Es hat das Potenzial, Regenerations- und Anpassungsmechanismen anzuregen und so zur Plastizität des Nervensystems beizutragen. Das Training ermöglicht eine individuelle und an die Tagesform angepasste Umsetzung und zeichnet sich durch einen geringen Material- und Zeitaufwand sowie eine gute Reproduzierbarkeit aus. Das SMT findet schon lange Anklang in der Rehabilitation sowie der Verletzungs- und Sturzprophylaxe. In den vergangenen Jahren wurde es auch vermehrt im Bereich der Erwachsenenonkologie zur Verbesserung der oftmals weitreichenden therapiebedingten Beeinträchtigungen der unteren Extremitäten, wie z. B. eine verminderte Gleichgewichtsfähigkeit, umgesetzt. Auch an Krebs erkrankte Kinder und Jugendliche sind häufig, u. a. infolge einer Chemotherapie-induzierten Polyneuropathie (CIPN), von den genannten Beeinträchtigungen in der unteren Extremität betroffen. Diese können sie auch noch lange nach der medizinischen Therapie daran hindern, ausreichend körperlich aktiv zu sein. SMT hat in diesem Kontext das Potenzial, adäquate sensorische und motorische Voraussetzungen für ein ausreichendes Aktivitätsniveau zu schaffen. Mit dem Ziel einer kindgerechten, motivierenden und individuellen Umsetzung des SMT wurde am Departement für Sport, Bewegung und Gesundheit der Universität Basel ein spezielles Trainingskonzept für die Kinderonkologie entwickelt. Mit einer Drehscheibe können die Kinder die Übungen kreativ und spielerisch zusammensetzen und so die Schwierigkeit individuell an ihre Tagesform nach der Therapie anpassen. Die Umsetzbarkeit des Trainingskonzepts wurde in einer 4-wöchigen Pilotstudie im Rahmen eines etablierten pädiatrisch-onkologischen Nachsorgesportprogramms der Deutschen Sporthochschule Köln im Kinderkrankenhaus Amsterdamer Straße Köln erprobt. Es nahmen 6 Kinder und Jugendliche teil. Die vorläufigen Ergebnisse der Pilotstudie und ein Fallbeispiel zeigen, dass das kindgerechte und spielerische SMT nach einer Krebserkrankung im Kindesalter ohne Zwischenfälle umsetzbar ist und eine spezifische und wertvolle Ergänzung der pädiatrisch-onkologischen Bewegungstherapie darstellen kann.

In sensorimotor training (SMT), in this case balance training as a sub-category of SMT, exercises are carried out on different surfaces and in different standing positions. SMT has the potential to induce regenerative and adaptive mechanisms, contributing to the plasticity of the nervous system. While the effort and material involved for this exercise modality is minimal, effects remain high and reproducibility is good. It can be adjusted individually to the participant's daily performance level. To date, SMT has been conducted in the context of rehabilitation as well as injury and fall prevention. In recent years, SMT has also been successfully implemented in adult oncology in order to improve common impairments of the lower extremities, such as reduced balance control. Children after inpatient oncological treatment also suffer from various mobility-related impairments of their lower extremities which can lead to further physical inactivity. These impairments may occur as a result of chemotherapy induced peripheral neuropathy (CIPN). SMT seems to have the potential to improve sensory and motor dysfunctions, contributing to higher physical activity in general. With the objective of implementing a child-friendly, motivating and individual SMT, a specific training concept for paediatric oncology was developed at the Department of Sport, Exercise and Health at the University of Basel. In this training concept, children use a turntable to compose the sensorimotor exercises based on their daily performance level. The feasibility of the training concept was tested in a 4-week pilot study, conducted within an established exercise program after cancer treatment of the German Sport University Cologne in the Children's Hospital Amsterdamer Strasse Cologne. 6 children and adolescents after oncological treatment took part. The preliminary results of the pilot study and a case example show that a child-friendly and playful SMT after paediatric oncological disease is feasible without occurrence of adverse events. Therefore, SMT might be a valuable and targeted training modality supplementing exercise therapy in paediatric oncology.

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%.

Gabriele Gauß · Sabine Kesting · Ursula Creutzig · Freerk Baumann · Joachim Boos · Uta Dirksen · Katharina Eckert · Robert Erschig · Pablo Hernáiz Driever · IngoMenrath · Aram Prokop · Dominik Schneider · Jannos Siaplaouras · Hannah Stalf · Arne Streitbürger · Andreas Wiener · JoachimWiskemann · Torge Wittke · Miriam Götte 1 Zentrum für Kinderund Jugendmedizin, Kinderheilkunde 3, Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Essen, Deutschland; 2 Deutsches Konsortium für Translationale Krebsforschung, Standort Essen, Essen, Deutschland; 3 Fakultät für Sportund Gesundheitswissenschaften, Lehrstuhl für Präventive Pädiatrie, Technische Universität München, München, Deutschland; München Klinik Schwabing, Klinik und Poliklinik für Kinderund Jugendmedizin, Kinderklinik München Schwabing, Technische Universität München, München Klinik gGmbH und Klinikum rechts der Isar (AöR), München, Deutschland; 5 Abteilung für Pädiatrische Hämatologie und Onkologie, Medizinische Hochschule Hannover, Hannover, Deutschland; 6 Klinik für Innere Medizin I, Uniklinik Köln, Köln, Deutschland; WestfälischeWilhelms-Universität Münster, Münster, Deutschland; 8 Klinik für Tumororthopädie und Sarkomchirurgie, Universitätsklinikum Essen, Essen, Deutschland; 9 IST-Hochschule für Management, Düsseldorf, Deutschland; 10 Rehaklinik Katharinenhöhe, Schönwald im Schwarzwald, Deutschland; 11 Pädiatrische Klinik mit Schwerpunkt Onkologie und Hämatologie, Charité – Universitätsmedizin Berlin, Berlin, Deutschland; 12 Klinik für Kinderund Jugendmedizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Deutschland; 13 Kinderund Jugendmedizin, Helios Kliniken Schwerin, Schwerin, Deutschland; 14 Klinik für Kinderund Jugendmedizin, KlinikumDortmund, Dortmund, Deutschland; 15 Kinderkardiologie, Praxis am Herz-JesuKrankenhaus, Fulda, Deutschland; 16 Pädiatrische Onkologie, Hämatologie und Hämaostaseologie, Universitätsklinikum Frankfurt amMain, Frankfurt amMain, Deutschland; 17 Klinik für Partikeltherapie, Universitätsklinikum Essen, Westdeutsches ProtonentherapiezentrumEssen (WPE), Westdeutsches Tumorzentrum (WTZ), Essen, Deutschland; 18 Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg, AbteilungMedizinische Onkologie, UniversitätsklinikumHeidelberg, Heidelberg, Deutschland; 19 Krukenberg Krebszentrum Halle, UniversitätsklinikumHalle (Saale), Halle (Saale), Deutschland

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.

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.