title: Synergistic interactions between camptothecin and EGFR or RAC1 inhibitors and between imatinib and Notch signaling or RAC1 inhibitors in glioblastoma cell lines.
abstract: OBJECTIVE
  The current treatment strategies for glioblastoma have limited health and survival benefits for the patients. A common obstacle in the treatment is chemoresistance. A possible strategy to evade this problem may be to combine chemotherapeutic drugs with agents inhibiting resistance mechanisms. The aim with this study was to identify molecular pathways influencing drug resistance in glioblastoma-derived cells and to evaluate the potential of pharmacological interference with these pathways to identify synergistic drug combinations.
  
  
  METHODS
  Global gene expressions and drug sensitivities to three chemotherapeutic drugs (imatinib, camptothecin and temozolomide) were measured in six human glioblastoma-derived cell lines. Gene expressions that correlated to drug sensitivity or resistance were identified and mapped to specific pathways. Selective inhibitors of these pathways were identified. The effects of six combinations of inhibitors and chemotherapeutic drugs were evaluated in glioblastoma-derived cell lines. Drug combinations with synergistic effects were also evaluated in non-cancerous epithelial cells.
  
  
  RESULTS
  Four drug combinations had synergistic effects in at least one of the tested glioblastoma-derived cell lines; camptothecin combined with gefitinib (epidermal growth factor receptor inhibitor) or NSC 23766 (ras-related C3 botulinum toxin substrate 1 inhibitor) and imatinib combined with DAPT (Notch signaling inhibitor) or NSC 23766. Of these, imatinib combined with DAPT or NSC 23766 did not have synergistic effects in non-cancerous epithelial cells. Two drug combinations had at least additive effects in one of the tested glioblastoma-derived cell lines; temozolomide combined with gefitinib or PF-573228 (focal adhesion kinase inhibitor).
  
  
  CONCLUSIONS
  Four synergistic and two at least additive drug combinations were identified in glioblastoma-derived cells. Pathways targeted by these drug combinations may serve as targets for future drug development with the potential to increase efficacy of currently used/evaluated chemotherapy.
authors.affiliation: Rudbeck Laboratory, Department of Radiation, Oncology and Radiation Science, Section of Oncology, Uppsala University, Dag Hammarskjölds väg 20, Uppsala, Sweden. linda.sooman@onkologi.uu.se
authors.forename: Linda
authors.initials: L
authors.lastname: Sooman
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
authors.forename: Claes
authors.initials: C
authors.lastname: Andersson
authors.forename: Hanna Göransson
authors.initials: HG
authors.lastname: Kultima
authors.forename: Anders
authors.initials: A
authors.lastname: Isaksson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
authors.forename: Erik
authors.initials: E
authors.lastname: Blomquist
authors.forename: Johan
authors.initials: J
authors.lastname: Lennartsson
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019295:Computational Biology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D046228:Microarray Analysis; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; C107953:RAC1 protein, human; D012334:RNA, Neoplasm; D051880:Receptors, Notch; D003606:Dacarbazine; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D020830:rac1 GTP-Binding Protein; D002166:Camptothecin; D000077204:Temozolomide