Examination of the cytotoxic and embryotoxic potential and underlying mechanisms of next-generation synthetic trioxolane and tetraoxane antimalarials
| Autor: | Paul M. O'Neill, Michael H. L. Wong, Ian M. Copple, James Chadwick, B. Kevin Park, James W. Firman, Bob van de Water, Stephen A. Ward, Maria Lurdes Santos Cristiano, Bram Herpers, Andreia D. Bringela, G. Donegan, Amy E. Mercer |
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| Rok vydání: | 2012 |
| Předmět: |
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Artemisinins Time Factors Artesunate Pharmacology Rats Sprague-Dawley chemistry.chemical_compound 0302 clinical medicine Cytotoxic T cell Tetraoxanes QD Artemisinin Genetics (clinical) media_common 0303 health sciences biology Cell Death Articles 3. Good health Teratogens 030220 oncology & carcinogenesis Caspases Molecular Medicine Female medicine.drug Drug Programmed cell death RM media_common.quotation_subject Iron Plasmodium falciparum Heme Cell Line 03 medical and health sciences Antimalarials parasitic diseases Genetics medicine Animals Humans Spiro Compounds Molecular Biology 030304 developmental biology biology.organism_classification Embryo Mammalian Rats Oxidative Stress chemistry |
| Zdroj: | Molecular Medicine; Vol 18 Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 1528-3658 1076-1551 |
| Popis: | Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria. |
| Databáze: | OpenAIRE |
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