Patrick Jesse

Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro

Viscum album (Mistletoe) is one of the most widely used alternative cancer therapies. Aqueous mistletoe extracts (MT) contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. Although MT is widely used, there is a lack of scientifically sound preclinical and clinical data. In this paper, we describe for the first time the in vivo efficacy and mechanism of action of MT in lymphoblastic leukemia. For this purpose, we first investigated both the cytotoxic effect and the mechanism of action of two standardized aqueous MTs (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) in a human acute lymphoblastic leukemia (ALL) cell line (NALM-6). MT-A, MT-P and ML-I inhibited cell proliferation as determined by Casy Count analysis at very low concentrations with MT-P being the most cytotoxic extract. DNA-fragmentation assays indicated that dose-dependent induction of apoptosis was the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). Both MTs significantly improved survival (up to 55.4 days) at all tested concentrations in contrast to controls (34.6 days) without side effects.

Iron containing anti-tumoral agents: unexpected apoptosis-inducing activity of a ferrocene amino acid derivative

PurposeDue to the severe problems accompanied with multiple drug resistance (MDR), agents that can induce apoptosis independently of death-suppressing proteins are required. Here, we show that the ferrocene derivative HUNI 068 is active against cancer cells and overcomes different mechanisms of multiple drug resistance (MDR).MethodsProliferation inhibition was determined by using a CASY®CellCounter. DNA fragmentation assay and annexin-V/PI binding assays measured apoptosis, and necrosis was excluded by LDH-release assay. Drug-resistant cell lines were generated to test the ability to overcome MDR. By real-time PCR, alterations in gene expression of treated cells were analyzed. The apoptosis pathway was investigated by immunoblotting and measurement of mitochondrial membrane permeability transition.ResultsHUNI 068 leads to proliferation inhibition and apoptosis mediation, but only minimal necrosis induction. Healthy leukocytes seem to be less affected than cancer cells. The compound overcomes drug resistance to vincristine and daunorubicin. Independence of p-glycoprotein and Bcl-2 overexpression is probable, and upregulation of the anti-Bcl-2 protein harakiri was seen. Combined treatment with vincristine leads to synergistic effects. In different primary tumor cells, HUNI 068 achieved acceptable effects where tolerance to some conventional drugs was shown. Induction of apoptosis is FADD-independent, but associated with a reduced mitochondrial membrane potential and activation of caspase-9, indicating the intrinsic apoptosis pathway via mitochondria.ConclusionsHUNI 068 is a promising new compound with activity even against MDR tumor cells. Further investigations into the class of ferrocene-derived agents might reveal compounds with improved activity for a more specific and safe anti-cancer therapy.

[FeIII(salophene)Cl], a potent iron salophene complex overcomes multiple drug resistance in lymphoma and leukemia cells

We demonstrate the cytotoxic potential of the Schiff base iron complex [Fe(III)(salophene)Cl] in vitro and ex vivo and illustrate its ability to overcome multiple drug resistance in vincristine and daunorubicine resistant leukemic cells (Nalm-6). Treatment of lymphoma cells (BJAB) with [Fe(III)(salophene)Cl] led to the exclusion of unspecific necrosis, a concentration-dependent inhibition of proliferation and a specific apoptotic cell death. We further detected a significant loss of the mitochondrial membrane potential in lymphoma cells and an up- and downregulation of various apoptosis relevant genes, respectively, indicating the involvement of the intrinsic mitochondrial pathway.

Apoptosis‐inducing activity of Helleborus niger in ALL and AML

Helleborus niger is used in the adjuvant treatment of different tumors in anthroposophical medicine. Indications include various types of brain tumors in children, as well as prostate cancer, leukemia and lymphoma. Our aim was to investigate the therapeutic effects of these extracts apart from the traditional use.

Anthroposophic supportive treatment in children with medulloblastoma receiving first-line therapy.

Background The use of anthroposophic medicine (AM) is popular in Central Europe, especially in German-speaking countries. Although these therapies are judged to be beneficial by many patients, there are few data with regard to the safety and efficacy in pediatric oncology. Several theoretical concerns have been published with regard to tumor enhancement or promotion of metastatic dissemination due to mistletoe. To test the indirect safety of supportive anthroposophic treatment accompanying the first-line treatment in children with medulloblastoma in this respect we performed a retrospective matched-pair analysis of patients with medulloblastoma treated by standard first-line radiochemotherapy with or without a concomitantly applied panel of AM including mistletoe. The question was whether the effectiveness of the first-line therapy is altered by AM. Procedure Seventeen patients with AM were matched in a 1:2 ratio with 34 patients from the database of the German HIT study group with regard to the criteria of diagnosis, age, status of metastatic dissemination, resection status, and first-line therapy. Results The overall survival after 10 years was 58.33% for the AM group and 57.14% for the control group, that is, showing no statistically significant difference (stratified Cox regression; P=0.6023). Event-free survival (including metastases) also did not differ between the groups (stratified Cox regression; P=0.4275). Conclusions AM consisting of different combinations of specific pharmacologic and nonpharmacologic interventions seems to be safe with respect to any potential negative impact on the first-line therapy. There is no evidence with regard to tumor enhancement. The effectiveness of the supportive AM cannot be assessed on the basis of these data.