Leveraging Cell Cycle Analysis in Anticancer Drug Discovery to Identify Novel Plasmodial Drug Targets

Sergei      Kozlov; Norman      C. Waters; Marina      Chavchich

Abstract

Cancer and malaria are life threatening diseases killing millions of people each year. In spite of our best efforts, both continue to resist full control and eradication. If untreated, both malaria and cancer can lead to death. Only a few antimalarial drugs have been developed over the last decades and new drugs are urgently needed to combat drug-resistant parasites. Significant progress has been made in understanding the molecular mechanisms of cancer and designing new anticancer therapies. However, similar to malaria, majority of cancers quickly develop resistance to single target-based therapy. Novel cancer therapeutics are being developed with the aim of targeting multiple signalling pathways in tumour cells, an approach that may be applicable to antimalarial therapy. In this review we compare cell signalling pathways targeted by cancer drugs with similar pathways in the malaria parasite. We placed particular emphasis on cell cycle regulation and cell cycle checkpoints since the associated molecular machinery controlling these processes are conserved in Plasmodium. Furthermore, a large number of cancer drugs target cell cycle control mechanisms and, therefore, these compounds may possess antimalarial activity. We tried to demonstrate that promising areas of anticancer drug development can be incorporated in the existing antimalarial drug discovery program as well as deepen our understanding of parasite biology.

Keywords: Plasmodium falciparum, malaria, cancer, cell cycle, signal transduction, kinases, apoptosis, checkpoint, artemisinin