Alami Nezha, Page Viviane, Yu Qingnan, Jerome Lori, Paterson Jesse, Shiry Laura, Leyland-Jones Brian
Oncology Department, McGill University, Montreal, QC, Canada.
Growth Horm IGF Res. 2008 Dec;18(6):487-96. doi: 10.1016/j.ghir.2008.04.002. Epub 2008 May 23.
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.
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.
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.
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.
胰岛素样生长因子结合蛋白3（IGFBP - 3）可通过不依赖胰岛素样生长因子I（IGF - I）的机制，在人类癌细胞中诱导抗增殖和促凋亡作用。本研究评估了重组人IGFBP - 3（rhIGFBP - 3）的抗肿瘤疗效及其在肺癌和结肠癌中与化疗药物的体内外相互作用。同时也检测了不同治疗方法对IGF - IR信号通路的影响。
分别使用rhIGFBP - 3作为单一药物或与卡铂或伊立替康联合，对小鼠Lewis肺癌（M - 3LL）和LoVo细胞系进行体外抗增殖试验。在M - 3LL体内模型中，小鼠分别接受rhIGFBP - 3（3或10mg/kg）、卡铂（25或50mg/kg）单独治疗或联合治疗。在LoVo异种移植模型中，小鼠接受rhIGFBP - 3（3、10或30mg/kg）、伊立替康（10或20mg/kg）单一疗法或联合疗法。
rhIGFBP - 3对M - 3LL模型呈现剂量依赖性肿瘤生长抑制作用，在测试的最高剂量下产生显著的肿瘤生长抑制。然而，它未能改善对卡铂的抗肿瘤反应。在LoVo结直肠癌异种移植模型中，rhIGFBP - 3在测试的最低剂量下产生显著的单药抑制作用，并增强了伊立替康的抗肿瘤活性。蛋白质免疫印迹分析表明，在体外M - 3LL和LoVo细胞系中，观察到的rhIGFBP - 3对肿瘤生长的抑制作用与Akt磷酸化水平降低相关。
我们的新发现为rhIGFBP - 3对肺癌和结肠癌模型的体内活性提供了证据，并揭示了其与化疗药物相互作用的新见解。rhIGFBP - 3的抗肿瘤作用与AKT信号通路的下调有关。
