Recombinant human insulin-like growth factor-binding protein 3 inhibits tumor growth and targets the Akt pathway in lung and colon cancer models.
OBJECTIVE
Insulin-like growth factor-binding protein 3 (IGFBP-3) can induce antiproliferative and proapoptotic effects in human cancer cells, by IGF-I independent mechanisms. The antitumor efficacy of recombinant human IGFBP-3 (rhIGFBP-3) and its interaction with chemotherapy in lung and colon cancers, in vitro and in vivo was evaluated. The effects of the different treatments on IGF-IR signaling pathways were also examined.


METHODS
Antiproliferative in vitro assay using rhIGFBP-3, as single agent or in combination with carboplatin or irinotecan against the murine Lewis Lung (M-3LL) and LoVo cell lines, respectively was performed. In the M-3LL model in vivo model, mice were treated with rhIGFBP-3 (3 or 10 mg/kg), carboplatin (25 or 50 mg/kg) alone or in combined treatments. In the LoVo xenograft model, mice were treated with rhIGFBP-3 (3, 10 or 30 mg/kg), irinotecan (10 or 20 mg/kg), as monotherapies or in combinations.


RESULTS
rhIGFBP-3 elicited a dose-dependent tumor growth inhibition on the M-3LL model and produced a significant tumor growth inhibition at the highest dose tested. However, it failed to improve the antitumor response to carboplatin. In the LoVo colorectal xenograft model, rhIGFBP-3 caused significant single-agent inhibitory effect and enhanced the antitumor activity of irinotecan at their lowest doses tested. Western blot analysis suggests that the observed tumor growth inhibition by rhIGFBP-3 correlates with decreased Akt phosphorylation in both M-3LL and LoVo cell lines in vitro.


CONCLUSIONS
Our novel findings provide evidence for in vivo activity of rhIGFBP-3 against lung and colon tumor models and reveal new insight into its interaction with chemotherapeutic drugs. The antitumor effects of rhIGFBP-3 are associated with a downregulation of AKT signaling.
Alami
Nezha
N
Oncology Department, McGill University, Montreal, QC, Canada. nezha.alami@vmir.org
Page
Viviane
V
Yu
Qingnan
Q
Jerome
Lori
L
Paterson
Jesse
J
Shiry
Laura
L
Leyland-Jones
Brian
B
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology / Q000627:therapeutic use; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D011994:Recombinant Proteins; D000077146:Irinotecan; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt; D002166:Camptothecin