title: Sensitivity and resistance towards isoliquiritigenin, doxorubicin and methotrexate in T cell acute lymphoblastic leukaemia cell lines by pharmacogenomics.
abstract: The development of drug resistance in cancer cells necessitates the identification of novel agents with improved activity towards cancer cells. In the present investigation, we compared the cytotoxicity of the chalcone flavonoide, isoliquiritigenin (ISL), with that of doxorubicin (DOX) and methotrexate (MTX) in five T cell acute lymphoblastic leukaemia (T-ALL) cell lines (Jurkat, J-Jhan, J16, HUT78 and Karpas 45). To gain insight into the molecular mechanisms which determine the response of T-ALL cells towards ISL, DOX and MTX, we applied array-based matrix comparative genomic hybridisation and microarray-based mRNA expression profiling and compared the genomic and transcriptomic profiles of the cell lines with their 50% inhibition (IC(50)) values for these three drugs. The IC(50) values for ISL did not correlate with those for DOX or MTX, indicating that ISL was still active in DOX- or MTX-unresponsive cell lines. Likewise, the genomic imbalances of chromosomal clones and mRNA expression profile significantly correlating with IC(50) values for ISL were different from thoses correlating with IC(50) values for DOX and MTX. In conclusion, ISL represents a cytotoxic natural product with activity towards T-ALL cell lines. There was no cross-resistance between ISL and DOX or MTX, and the genomic and transcriptomic profiles pointed to different molecular modes of action of ISL as compared to DOX and MTX, indicating that ISL may be a valuable adjunct for cancer therapy to treat otherwise drug-resistant tumours.
authors.affiliation: Department of Pharmaceutical Biology, University of Mainz, Mainz, Germany.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Youns
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Fu
authors.forename: Yuan-Gang
authors.initials: YG
authors.lastname: Zu
authors.forename: Anne
authors.initials: A
authors.lastname: Kramer
authors.forename: V Badireenath
authors.initials: VB
authors.lastname: Konkimalla
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000008:administration & dosage / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D046228:Microarray Analysis; D010597:Pharmacogenetics / Q000379:methods*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D047188:Chalcones; D012333:RNA, Messenger; D004317:Doxorubicin; C040920:isoliquiritigenin; D008727:Methotrexate