Simaomicin α: Effects on the Cell Cycle of Synchronized, Cultured Plasmodium falciparum

Abstract

Simaomicin a shows potent antimalarial activity in vitro and is known to be a cell-cycle effector. As erythrocytic schizogony of Plasmodium correlates with cell cycle events, we investigated the effect of simaomicin a on stage development of the malaria parasite Plasmodium falciparum. Simaomicin a interferes with normal parasite development in a time and concentration dependent manner. Parasites exposed to 2.5 nM simaomicin a at the ring stage or trophozoite stage showed disrupted development and immature schizont-like and segmenterlike forms were observed. However, schizont stage parasites were not affected by 2.5 nM simaomicin a. It is unclear whether mitosis involved in sequential parasite development occurred when parasites were exposed to simaomicin a at the ring or trophozoite stage. At a concentration of 5.0 nM, simaomicin a inhibited merozoite-trophozoite development. This concentration curtails p-LDH activity at all parasite stages, although its impact on the schizont stage is delayed for 24 hours.Keywords Simaomicin a , Plasmodium, malaria, cellcycle, synchronous culture During the course of our long-term and continuing programme of screening microbial metabolites, we have discovered various compounds that exhibit potent antimalarial activities [1ϳ6]. We previously reported that simaomicin a showed potent antimalarial activity in vitro [6]. Furthermore, we reported that it has bleomycininduced G2 checkpoint inhibitory activity against human Tcell leukemia-derived Jurkat cells [7].Erythrocytic schizogony of Plasmodium falciparum correlates with specific cell-cycle events, such as G1, S and M phases. However, several aspects remain poorly understood, particularly in connection with the G2 and M phases [8,9]. In the present study we demonstrate the stage-specific antimalarial activity of simaomicin a , although the mechanism of action remains unresolved. Consequently, simaomicin a may be useful in studying the cell-cycle of P. falciparum.The drug-sensitive P. falciparum strain FCR3 was cultured and synchronized using the D-sorbitol method [10] to produce specific parasite stages. At 24ϳ36 hours after the first synchronization, the parasites were synchronized again. At 36 hours after the second synchronization the last synchronization was completed. The cells were treated and then used for experimentation. Two or three D-sorbitol treatments were carried out to prepare ring-stage parasites (Ͼ90%) based on direct observation of parasite growth. For experimental purposes, parasite stages were determined as follows: Ring stage (0ϳ12 hours after last synchronization) which has a ring form; early-trophozoite stage (12ϳ24

Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products

“…It probably indicated that inhibition of P. falciparum cell is not or not only due to the inhibition of Pf PanK1. From previous report, this compound showed antimalarial activity in vitro and is known to be a cell-cycle effector in P. falciparum ( Ishiyama et al., 2008 ), whereas the exact mechanism is unrevealed. in human cancer cell, target of simaomicin α has been described to suppress the retinoblastoma protein phosphorylation and promotes apoptosis ( Koizumi et al., 2009 ).…”

Borrelidin, a potent antimalarial: stage-specific inhibition profile of synchronized cultures of Plasmodium falciparum

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Chemistry and biosynthesis of bacterial polycyclic xanthone natural products

“…80 Subsequently, in 2008, 57 was reported to affect stage development of the malaria parasite Plasmodium falciparum in a time- and concentration-dependent manner. 81 When T-cell leukemia Jurkat cells were treated with 57 of 3 nM, the number of cells in the G1 phase increased and those in G2-M phase decreased with an induced increase in cellular caspase-3 activity and DNA fragmentation. The latter phenomenon indicated the promotion of apoptosis.…”