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  • What does this mean for cancer therapy We found that

    2019-07-11

    What does this mean for cancer therapy? We found that components of the de novo pyrimidine synthesis pathway rarely mutate in cancer, clearly showing its importance. In our experimental models, the pathway, including DHODH itself, was primed to respond when the block in CoQ redox-cycling was removed. Inhibitors of DHODH are used in the clinic as anti-rheumatics (Olsen and Stein, 2004) and show efficacy in cancer settings either alone or in combination with anti-cancer agents (Brown et al., 2017, Mathur et al., 2017, Sykes et al., 2016, Shukla et al., 2017, Kim et al., 2017, Koundinya et al., 2018). A more effective therapeutic approach could involve intervention at the level of respiratory CIII. This would not only block DHODH activity and pyrimidine biosynthesis, but would also increase the generation of reactive oxygen species from the respiratory chain (Adam-Vizi and Chinopoulos, 2006, Murphy, 2009, Quinlan et al., 2012), striking the cancer cell on two fronts at once by way of combining the cell death inducing activity of excessive oxidative stress (Rohlena et al., 2011) with the cytostatic activity of DHODH inhibition. While anti-cancer agents directed at CIII exist (Le et al., 2007), their potential side effects on the hematopoietic and immune systems would need to be carefully evaluated (Anso et al., 2017). In conclusion, we show here that cancer BIIE 0246 molecular with dysfunctional OXPHOS due to mtDNA deficiency import mitochondria from the host to restore respiration and facilitate the DHODH-catalyzed conversion of DHO to orotate. Intriguingly, reactivation of CoQ redox-cycling is sufficient to drive DHODH and to allow cancer cells to form tumors. We propose that DHODH-mediated CoQ redox-cycling is an important link between de novo pyrimidine synthesis and respiration, and that it may be a promising target for broad-spectrum cancer therapy. This notion is corroborated by the emergence of tumor metabolism as a target for anti-cancer therapeutic strategies (Sullivan et al., 2016, Martinez-Outschoorn et al., 2017). Our reasoning is based on the concept that despite their high metabolic plasticity, that includes the ability to “import” mitochondria, cancer cells seem unable to “bypass” pyrimidine synthesis defects, presenting a novel aspects of cancer biology with potential therapeutic implications.
    STAR★Methods
    Introduction Malaria is one among the world\'s “big three diseases” (HIV/AIDS, TB, and malaria) that kill millions of people in the world. It is the most life threatening neglected disease [1]. This is majorly caused by the species of plasmodium protozoa [2], [3] which are being carried to vertebrate hosts like mice, monkey, and human by anopheles mosquito from infectious ones. According to the world malaria report 2015 (WHO), approximately 214 million cases of malaria were found in which 438 000 deaths occurred, ∼90% of these occurred in sub-Saharan Africa and 3.2 billion people residing in 97 countries were estimated to be at risk of malaria [4]. Since pregnant woman and children below 5 years are very prone to this disease [5], so about 1300 children every day or one child almost every minute die due to malaria. Nonimmune travelers from malaria free areas when move to malaria affected areas often fall prey of this disease. The five species of plasmodium that affect human erythrocytes are: P. falciparum, P. vivax, P. ovale, P. knowlesi, and P. malariae. On global account P. falciparum and P. vivax constitute 93% of malarial infections [6]. Among these, P. falciparum is considered to be the most lethal species. Chemotypically different types of drugs have been developed in order to curb this deadly disease. Pharmacological science has always struggled to abolish this diseases while restricting it at various stages like, hyponozoitic, merozoitic, trophozoitic and schizontic stages. Another approach to abrogate this disease includes the inhibition of the various essential enzymes for the metabolic activity of the plasmodium parasite. Since pyrimidines are fundamental metabolites that are precursors for DNA and RNA biosynthesis, the enzymes involved in the pyrimidine biosynthetic pathway can be the successful antimalarial drug targets. Many of the clinically admissible antimalarial drugs directly or indirectly affect the pyrimidine metabolism, this may also be the reason of their antimalarial effect. The antimalarial drugs reported so far worked only for certain period of time and later failed due to the rising resistance of the parasite against these drugs. This issue made the search for new drugs a continuous process. It also compelled human to use the combination therapy of more than one drugs to treat malaria.