期刊
GROWTH HORMONE & IGF RESEARCH
卷 18, 期 6, 页码 487-496出版社
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.ghir.2008.04.002
关键词
rhIGFBP-3; Lung cancer; Colon cancer; Interaction with chemotherapy
资金
- Research Fund from Insmed Incorporated
Objective: Insulin-like growth factor-binding protein 3 (IGFBP-3) can induce antiproliferative and proapoptotic effects in human cancer cells, by IGF-1 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. Design: 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 ill vitro. Conclusions: Our novel findings provide evidence for ill 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. (C) 2008 Elsevier Ltd. All rights reserved.
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