title: Enhancement of doxorubicin cytotoxicity of human cancer cells by tyrosine kinase inhibition of insulin receptor and type I IGF receptor.
abstract: The type I insulin-like growth factor receptor (IGF1R) contributes to cancer cell biology. Disruption of IGF1R signaling alone or in combination with cytotoxic agents has emerged as a new therapeutic strategy. Our laboratory has shown that sequential treatment with doxorubicin (DOX) and anti-IGF1R antibodies significantly enhanced the response to chemotherapy. In this study, we examined whether inhibition of the tyrosine kinase activity of this receptor family would also enhance chemotherapy response. Cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF1R and insulin receptor (InsR) kinase activity and downstream activation of ERK1/2 and Akt in MCF-7 and LCC6 cancer cells. PQIP inhibited both monolayer growth and anchorage-independent growth in a dose-dependent manner. PQIP did not induce apoptosis, but rather, PQIP treatment was associated with an increase in autophagy. We examined whether sequential or combination therapy of PQIP with DOX could enhance growth inhibition. PQIP treatment together with DOX or DOX followed by PQIP significantly inhibited anchorage-independent growth in MCF-7 and LCC6 cells compared to single agent alone. In contrast, pre-treatment with PQIP followed by DOX did not enhance the cytotoxicity of DOX in vitro. Furthermore, OSI-906, a PQIP derivative, inhibited IGF-I signaling in LCC6 xenograft tumors in vivo. When given once a week, simultaneous administration of OSI-906 and DOX significantly enhanced the anti-tumor effect of DOX. In summary, these results suggest that timing and duration of the IGF1R/InsR tyrosine kinase inhibitors with chemotherapeutic agents should be evaluated in clinical trials. Long-term disruption of IGF1R/InsR may not be necessary when combined with cytotoxic chemotherapy.
authors.affiliation: Masonic Cancer Center, University of Minnesota, MMC 806, 420 Delaware St SE, Minneapolis, MN 55455, USA.
authors.forename: Xianke
authors.initials: X
authors.lastname: Zeng
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Annabell
authors.initials: A
authors.lastname: Oh
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C523453:3-(3-(4-methylpiperazin-1-yl)cyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-8-ylamine; C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D011719:Pyrazines; D004317:Doxorubicin; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin