Correlation between Cyclin Dependent Kinases and Artemisinin-Induced Dormancy in Plasmodium falciparum In Vitro.
BACKGROUND
Artemisinin-induced dormancy provides a plausible explanation for recrudescence following artemisinin monotherapy. This phenomenon shares similarities with cell cycle arrest where cyclin dependent kinases (CDKs) and cyclins play an important role.


METHODS
Transcription profiles of Plasmodium falciparum CDKs and cyclins before and after dihydroartemisinin (DHA) treatment in three parasite lines, and the effect of CDK inhibitors on parasite recovery from DHA-induced dormancy were investigated.


RESULTS
After DHA treatment, parasites enter a dormancy phase followed by a recovery phase. During the dormancy phase parasites up-regulate pfcrk1, pfcrk4, pfcyc2 and pfcyc4, and down-regulate pfmrk, pfpk5, pfpk6, pfcrk3, pfcyc1 and pfcyc3. When entering the recovery phase parasites immediately up-regulate all CDK and cyclin genes. Three CDK inhibitors, olomoucine, WR636638 and roscovitine, produced distinct effects on different phases of DHA-induced dormancy, blocking parasites recovery.


CONCLUSIONS
The up-regulation of PfCRK1 and PfCRK4, and down regulation of other CDKs and cyclins correlate with parasite survival in the dormant state. Changes in CDK expression are likely to negatively regulate parasite progression from G1 to S phase. These findings provide new insights into the mechanism of artemisinin-induced dormancy and cell cycle regulation of P. falciparum, opening new opportunities for preventing recrudescence following artemisinin treatment.
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.|Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Karen-Ann
KA
Gray
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.|Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Karryn J
KJ
Gresty
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.
Nanhua
N
Chen
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.|School of Biochemistry, University of Queensland, Brisbane, Australia.
Veronica
V
Zhang
US Naval Academy, Annapolis, Maryland, United States of America.
Clare E
CE
Gutteridge
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.|Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Christopher L
CL
Peatey
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.
Marina
M
Chavchich
Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
Norman C
NC
Waters
Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia.|Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Qin
Q
Cheng
D000818:Animals; D037621:Artemisinins / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D017125:Genes, Protozoan; D008018:Life Cycle Stages / Q000187:drug effects; D018512:Parasitemia / Q000235:genetics / Q000469:parasitology; D010271:Parasites / Q000187:drug effects / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D037621:Artemisinins; D016213:Cyclins; D047428:Protein Kinase Inhibitors; C039060:artenimol; C031327:artemisinin; D018844:Cyclin-Dependent Kinases