Dictyostelium discoideum to human cells: pharmacogenetic studies demonstrate a role for sphingolipids in chemoresistance.
Resistance to chemotherapy is a major obstacle for the treatment of cancer and a subject of extensive research. Numerous mechanisms of drug resistance have been proposed, and they differ for different drugs. Nevertheless, it is clear that our understanding of this important problem is still incomplete, and that new targets for modulating therapy still await discovery. The attractive biology and the availability of powerful molecular techniques have made the cellular slime mold Dictyostelium discoideum, a powerful non-mammalian model for drug target discovery, and the problem of drug resistance. To understand the molecular basis of chemoresistance to the widely used drug cisplatin, both genetic and pharmacological approaches have been applied to this versatile experimental system. These studies have resulted in the identification of novel molecular pathways which can be used to increase the efficacy of cisplatin, and brought attention to the role of sphingolipids in mediating the cellular response to chemotherapeutic drugs. In the following review, we will describe the history and utility of D. discoideum in pharmacogenetics, and discuss recent studies which focus attention on the role of sphingolipids in chemotherapy and chemoresistance.
Alexander
Stephen
S
Division of Biological Sciences, 303 Tucker Hall, University of Missouri, Columbia, MO 65211-7400, USA. alexanderst@missouri.edu
Min
Junxia
J
Alexander
Hannah
H
D000446:Aldehyde-Lyases / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004023:Dictyostelium / Q000187:drug effects / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010597:Pharmacogenetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D013107:Sphingolipids / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099157:Sphingosine Kinase
D000446:Aldehyde-Lyases; D002945:Cisplatin; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D048031:JNK Mitogen-Activated Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D048051:p38 Mitogen-Activated Protein Kinases; D000099157:Sphingosine Kinase; C022649:sphingosine 1-phosphate lyase (aldolase)