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Posts Tagged ‘kinase inhibitor’

Breakthrough in Malaria Treatment in the Run Up to World Malaria Day

April 21, 2011 Leave a comment

Ahead of World Malaria Day (25 April), EU-funded researchers have discovered that drugs originally designed to inhibit the growth of cancer cells can also kill the parasite that causes malaria. They believe this discovery could open up a new strategy for combating this deadly disease, which, according to World Health Organisation statistics, infected around 225 million and killed nearly 800,000 people worldwide in 2009.

Efforts to find a treatment have so far been hampered by the parasite’s ability to quickly develop drug resistance. The research involved four projects funded by the EU (ANTIMAL, BIOMALPAR, MALSIG and EVIMALAR) and was led by laboratories in the UK, France and Switzerland with partners from Belgium, Germany, Denmark, Greece, Spain, Italy, Netherlands, Portugal, and Sweden, along with many developing nations severely affected by malaria.

Research, Innovation and Science Commissioner Máire Geoghegan-Quinn said: “This discovery could lead to an effective anti-malaria treatment that would save millions of lives and transform countless others. This demonstrates yet again the added value both of EU-funded research and innovation in general and of collaboration with researchers in developing countries in particular. The ultimate goal is the complete eradication of the global scourge of malaria and collaborative work across many borders is the only way of confronting such global challenges effectively.”

Cancer drugs to kill malaria parasite

Malaria is caused by a parasite called Plasmodium, which is transmitted via the bites of infected mosquitoes. In the human body, the parasites reproduce in the liver, and then infect and multiply in red blood cells. Joint research led by EU-funded laboratories at the Inserm-EPFL Joint Laboratory, Lausanne, (Switzerland/France), Wellcome Trust Centre for Molecular parasitology, University of Glasgow (Scotland), and Bern University (Switzerland) showed that, in order to proliferate, the malaria parasite depends upon a signalling pathway present in the host’s liver cells and in red blood cells. They demonstrated that the parasite hijacks the kinases (enzymes) that are active in human cells, to serve its own purposes. When the research team used cancer chemotherapy drugs called kinase inhibitors to treat red blood cells infected with malaria , the parasite was stopped in its tracks.

A new strategy opens up

Until now the malaria parasite has managed to avoid control by rapidly developing drug resistance through mutations and hiding from the immune system inside liver and red blood cells in the body of the host, where it proliferates. The discovery that the parasite needs to hijack some enzymes from the cell it lives in opens up a whole new strategy for fighting the disease. Instead of targeting the parasite itself, the idea is to make the host cell environment useless to it, by blocking the kinases in the cell. This strategy deprives the parasite of a major modus operandi for development of drug resistance.

Several kinase-inhibiting chemotherapy drugs are already used clinically in cancer therapy, and many more have already passed phase-I and phase II clinical trials. Even though these drugs have toxic side-effects, they are still being used over extended periods for cancer treatment. In the case of malaria, which would require a shorter treatment period, the problem of toxicity would be less acute. Researchers are proposing therefore that these drugs should be evaluated immediately for anti-malarial properties, drastically reducing the time and cost required to put this new malaria-fighting strategy into practice.

The next steps will include mobilising public and industrial partners to verify the efficacy of kinase inhibitors in malaria patients and to adjust the dose through clinical trials, before the new treatments can be authorised and made available to malaria patients worldwide.

Journal Reference:

  1. Audrey Sicard, Jean-Philippe Semblat, Caroline Doerig, Romain Hamelin, Marc Moniatte, Dominique Dorin-Semblat, Julie A. Spicer, Anubhav Srivastava, Silke Retzlaff, Volker Heussler, Andrew P. Waters, Christian Doerig. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytesCellular Microbiology, 2011; DOI:10.1111/j.1462-5822.2011.01582.x
  2. The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by European Commission, Research & Innovation DG, viaAlphaGalileo.
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Malaria’s Weakest Link: Class of Chemotherapy Drugs Also Kills the Parasite That Causes Malaria

April 21, 2011 Leave a comment

A group of researchers from EPFL’s Global Health Institute (GHI) and Inserm (Institut National de la Santé et de la Recherche Médicale, the French government agency for biomedical research) has discovered that a class of chemotherapy drugs originally designed to inhibit key signaling pathways in cancer cells also kills the parasite that causes malaria. The discovery could quickly open up a whole new strategy for combating this deadly disease.

The research, published online in the journal Cellular Microbiology, shows that the malaria parasite depends upon a signaling pathway present in the host — initially in liver cells, and then in red blood cells — in order to proliferate. The enzymes active in the signaling pathway are not encoded by the parasite, but rather hijacked by the parasite to serve its own purposes. These same pathways are targeted by a new class of molecules developed for cancer chemotherapy known as kinase inhibitors. When the GHI/Inserm team treated red blood cells infected with malaria with the chemotherapy drug, the parasite was stopped in its tracks.

Professor Christian Doerig and his colleagues tested red blood cells infected with Plasmodium falciparum parasites and showed that the specific PAK-MEK signaling pathway was more highly activated in infected cells than in uninfected cells. When they disabled the pathway pharmacologically, the parasite was unable to proliferate and died. Applied in vitro, the chemotherapy drug also killed a rodent version of malaria (P. berghei), in both liver cells and red blood cells. This indicates that hijacking the host cell’s signaling pathway is a generalized strategy used by malaria, and thus disabling that pathway would likely be an effective strategy in combating the many strains of the parasite known to infect humans.

Malaria infects 250 million and kills 1-3 million people every year worldwide. Efforts to find a treatment have been marred by the propensity of the parasite to quickly develop drug resistance through selection of mutations. Once in the body, it hides from the immune system inside liver and blood cells, where it proliferates. The discovery that the parasite hijacks a signaling pathway in the host cell opens up a whole new strategy for fighting the disease. Instead of targeting the parasite itself, we could make the host cell environment useless to it, thus putting an end to the deadly cycle. Because this strategy uniquely targets host cell enzymes, the parasite will be deprived of a major modus operandi for development of drug resistance — selection of mutations in the drug target.

Several kinase-inhibiting chemotherapy drugs are already used clinically, and many more have passed stage 1 and stage 2 clinical trials. Even though these drugs have toxic effects, they are still being used or considered for use over extended periods for cancer treatment. Using them to combat malaria would involve a much shorter treatment period, making the problem of toxicity less acute. The authors of the study suggest evaluating these drugs for antimalarial properties, thus drastically reducing the time and cost required to put this new malaria-fighting strategy into practice.

Journal Reference:

  1. Audrey Sicard, Jean-Philippe Semblat, Caroline Doerig, Romain Hamelin, Marc Moniatte, Dominique Dorin-Semblat, Julie A. Spicer, Anubhav Srivastava, Silke Retzlaff, Volker Heussler, Andrew P. Waters, Christian Doerig. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytesCellular Microbiology, 2011; DOI:10.1111/j.1462-5822.2011.01582.x
  2. The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Ecole Polytechnique Federale de Lausanne (EPFL), viaAlphaGalileo.