title: Anti-malarial effect of semi-synthetic drug amitozyn.
abstract: BACKGROUND
  Malaria caused by Plasmodium falciparum is the most virulent form of malaria, leading to approximately a half million deaths per year. Chemotherapy continues to be a key approach in malaria prevention and treatment. Due to widespread parasite drug resistance, identification and development of new anti-malarial compounds remains an important task of malarial parasitology. The semi-synthetic drug amitozyn, obtained through alkylation of major celandine (Chelidonium majus) alkaloids with N,N'N'-triethylenethiophosphoramide (ThioTEPA), is a widely used Eastern European folk medicine for the treatment of various tumours. However, its anti-malarial effect has never been studied.
  
  
  METHODS
  The anti-malarial effects of amitozyn alone and in combination with chloroquine, pyrimethamine and artemisinin on the blood stages of P. falciparum were analysed. The cytostatic effects of amitozyn on parasites and various cancerous and non-cancerous human cells were compared and their toxic effects on unparasitized human red blood cells were analysed.
  
  
  RESULTS
  Obtained results demonstrate that amitozyn effectively inhibits the growth of blood-stage parasites with IC50 9.6 ± 2, 11.3 ± 2.8 and 10.8 ± 1.8 μg/mL using CS2, 3G8 and NF54 parasite lines, respectively. The median IC50 for 14 tested human cell lines was 33-152 μg/mL. Treatment of uninfected red blood cells with a high dose of amitozyn (500 μg/mL) did not change cell morphology, demonstrating its non-toxicity for erythrocytes. The synergistic impact of the amitozyn/chloroquine combination was observed at growth inhibition levels of 10-80 %, while demonstrating a nearly additive effect at a growth inhibition level of 90 %. The combination of amitozyn with pyrimethamine has a synergistic effect at growth inhibition levels of 10-70 % and a nearly additive effect at a growth inhibition level of 90 %. The synergistic anti-malarial effect of the amitozyn/artemisinin combination was observed at growth inhibition levels of 10-40 % and a nearly additive effect at growth inhibition levels of 50-90 %.
  
  
  CONCLUSIONS
  These in vitro results suggest that the semi-synthetic drug amitozyn, typically used for the treatment of tumours, is a potential anti-malarial candidate and warrants more detailed laboratory and pre-clinical investigations.
authors.affiliation: Department of Biomedical Science, Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA. tchernuk@yahoo.com.|Department of Biological Sciences, Youth Academy of Sciences, Kiev, Ukraine. tchernuk@yahoo.com.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Tcherniuk
authors.affiliation: Department of Biomedical Science, Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA. ochesnokov@health.fau.edu.
authors.forename: Olga
authors.initials: O
authors.lastname: Chesnokova
authors.affiliation: Department of Biomedical Science, Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA. ioleinikov@fau.edu.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Oleinikov
authors.affiliation: Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kiev, Ukraine. potopalsky@imbg.org.ua.|Institute of Health Promotion and Rebirth of People of Ukraine, Kiev, Ukraine. potopalsky@imbg.org.ua.
authors.forename: Anatoly I
authors.initials: AI
authors.lastname: Potopalsky
authors.affiliation: Department of Biomedical Science, Charles E Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, USA. aoleinikov@health.fau.edu.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Oleinikov
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D028281:Chelidonium / Q000737:chemistry; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents