(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.

Branched-chain amino acid transaminase 1 regulates glioblastoma cell plasticity and contributes to immunosuppression.

BACKGROUND: Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) was shown to drive the growth of glioblastoma and other cancers;however, its oncogenic mechanism remains poorly understood. METHODS: Using human tumor data, cell line models and orthotopic immuno-competent and -deficient mouse models, we investigated the phenotypic and mechanistic effects of BCAT1 on glioblastoma cell state and immunomodulation. RESULTS: Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of ten-eleven translocation demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8+ cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. CONCLUSIONS: Our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.

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.

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.

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.