Toxic Effects of Amanitins: Repurposing Toxicities toward New Therapeutics.

The consumption of mushrooms has become increasingly popular, partly due to their nutritional and medicinal properties. This has increased the risk of confusion during picking, and thus of intoxication. In France, about 1300 cases of intoxication are observed each year, with deaths being mostly attributed to Amanita phalloides poisoning. Among amatoxins, α- and ß-amanitins are the most widely studied toxins. Hepatotoxicity is the hallmark of these compounds, leading to hepatocellular failure within three days of ingestion. The toxic mechanisms of action mainly include RNA polymerase II inhibition and oxidative stress generation, leading to hepatic cell apoptosis or necrosis depending on the doses ingested. Currently, there is no international consensus concerning Amanita phalloides poisoning management. However, antidotes with antioxidant properties remain the most effective therapeutics to date suggesting the predominant role of oxidative stress in the pathophysiology. The partially elucidated mechanisms of action may reveal a suitable target for the development of an antidote. The aim of this review is to present an overview of the knowledge on amanitins, including the latest advances that could allow the proposal of new innovative and effective therapeutics.

HDP-101, an Anti-BCMA Antibody-Drug Conjugate, Safely Delivers Amanitin to Induce Cell Death in Proliferating and Resting Multiple Myeloma Cells.

Despite major treatment advances in recent years, patients with multiple myeloma inevitably relapse. The RNA polymerase II complex has been identified as a promising therapeutic target in both proliferating and dormant cancer cells. Alpha-amanitin, a toxin so far without clinical application due to high liver toxicity, specifically inhibits this complex. Here, we describe the development of HDP-101, an anti-B-cell maturation antigen (BCMA) antibody conjugated with an amanitin derivative. HDP-101 displayed high efficacy against both proliferating and resting myeloma cells in vitro, sparing BCMA-negative cells. In subcutaneous and disseminated murine xenograft models, HDP-101 induced tumor regression at low doses, including durable complete remissions after a single intravenous dose. In cynomolgus monkeys, HDP-101 was well tolerated with a promising therapeutic index. In conclusion, HDP-101 safely and selectively delivers amanitin to myeloma cells and provides a novel therapeutic approach to overcome drug resistance in this disease.

Amanitinas / Amanitines

La intoxicación por consumo de hongos es un fenómeno estacional que se produce con relativa frecuencia en áreas geográficas donde es habitual su consumo, en especial de especies silvestres. Dependiendo del tipo de hongo ingerido pueden aparecer distintos cuadros clínicos (gastrointestinal, nefrotóxico, alucinatorio, etc.). El cuadro más grave es el hepatotóxico, asociado a una alta mortalidad, y causado por hongos que contienen amatoxinas (síndrome ciclopeptídico). Presentamos una revisión actualizada de las características de las amatoxinas, su cinética y mecanismo de acción, los métodos utilizados para su determinación analítica, así como las diferentes opciones para el tratamiento de la intoxicación (AU)

Mushroom poisoning is a seasonal phenomenon that occurs relatively frequently in geographical areas where its consumption is common. Depending on the type of fungus ingested different clinical symptoms (gastrointestinal, nephrotoxic, hallucinatory, etc.) can occur. Hepatotoxic syndrome caused by fungi containing amatoxins is the most serious condition, associated to high mortality. We present an updated review of amatoxins characteristics, kinetics, mechanism of action, methods used for analytical determination, as well as the different options for the treatment of poisoning (AU)

Tumor therapy with Amanita phalloides (death cap): stabilization of B-cell chronic lymphatic leukemia.

BACKGROUND: Molecular events that cause tumor formation upregulate a number of HOX genes, called switch genes, coding for RNA polymerase II transcription factors. Thus, in tumor cells, RNA polymerase II is more active than in other somatic cells. Amanita phalloides contains amanitin, inhibiting RNA polymerase II. Partial inhibition with amanitin influences tumor cell--but not normal cell--activity. OBJECTIVES: To widen the treatment spectrum, homeopathic dilutions of Amanita phalloides, containing amanitin, were given to a patient with leukemia. Monitoring the leukemic cell count, different doses of amanitin were given. RESULTS: The former duplication time of leukemic cells was 21 months. Within a period of 21 months, the cell count is stabilized to around 10(5)/µL. No leukemia-associated symptoms, liver damage, or continuous erythrocyte deprivation occur. CONCLUSIONS: This new principle of tumor therapy shows high potential to provide a gentle medical treatment.

Hemoperfusion with alpha-amanitin: an in vitro study.

The authors carried out sixteen hemoperfusions with alpha-amanitin in vitro in a closed system using active charcoal, Amberlite XAD-2 and Amberlite XAD-4 in hemoperfusion capsules. As a perfusion solution 4 liters of 0.9% NaCl solution was used. The alpha-amanitin concentration in the solution was 8.3 +/- 0.36 mg/L. Individual hemoperfusion lasted 5 hours. Two hundred and forty minutes of Amberlite XAD-2 hemoperfusion led to the zero values of alpha-amanitin concentration in 0.9% NaCl solution. When using active charcoal the adsorption capacity of the hemoperfusion capsule was already exhausted at 120 min. The results gathered suggest that the most effective alpha-amanitin hemoperfusion in vitro was obtained with Amberlite XAD-2 and the least effective with active charcoal. The authors recommend the use of hemoperfusion with Amberlite XAD-2 for acute intoxication with Amanita phalloides in humans up to 24-36 hours after poisoning.

Strongly enhanced toxicity of the mushroom toxin alpha-amanitin by an amatoxin-specific Fab or monoclonal antibody.

A monoclonal antibody, with high affinity against the mushroom toxin alpha-amanitin, was prepared. Administration of the Fab fragment of the monoclonal antibody to mice caused a 50-fold increase in alpha-amanitin toxicity. Electron micrographs showed normal appearance of hepatocytes but typical, amanitin-induced lesions in cells of the proximal convoluted tubules of the kidney. The pronounced nephrotoxicity is mainly explained by glomerular filtration and tubular reabsorption of the Fab-amatoxin complex and, to a lesser extent, of the immunoglobulin-amatoxin complex, which is still c. Twice as toxic as free alpha-amanitin. To our knowledge this is the first reported case where immunoglobulins or their fragments enhance rather than decrease the activity of a toxin. Accordingly, immunotherapy of Amanita mushroom poisoning in humans does not appear promising.