Strömberg Thomas, Ekman Simon, Girnita Leonard, Dimberg Lina Y, Larsson Olle, Axelson Magnus, Lennartsson Johan, Hellman Ulf, Carlson Kristina, Osterborg Anders, Vanderkerken Karin, Nilsson Kenneth, Jernberg-Wiklund Helena
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Blood. 2006 Jan 15;107(2):669-78. doi: 10.1182/blood-2005-01-0306. Epub 2005 Sep 15.
Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R beta-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G(2)/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.
新出现的证据表明，胰岛素样生长因子-1受体（IGF-1R）是多发性骨髓瘤（MM）中肿瘤细胞存活和对细胞毒性治疗耐药的重要介质。最近，环木脂素家族成员已被证明能选择性抑制IGF-1Rβ链的受体酪氨酸激酶（RTK）活性。使用一组13种MM细胞系和来自10例MM患者的新鲜纯化肿瘤细胞，在体外研究了环木脂素鬼臼苦素（PPP）的作用。PPP明显抑制了所有MM细胞系以及在有或无骨髓基质细胞存在下培养的原发性MM样本的生长。PPP诱导细胞在G(2)/M期大量积累并增加凋亡。重要的是，IGF-1、IGF-2、胰岛素或IL-6并未降低PPP的抑制作用。如体外激酶测定所示，PPP下调IGF-1 RTK活性而不抑制胰岛素RTK活性。这导致Erk1/2磷酸化减少和细胞周期蛋白依赖性激酶（CDK1）活性降低。此外，mcl-1和survivin的表达也降低。综上所述，我们认为使用环木脂素PPP干扰IGF-1 RTK为MM提供了一种新的选择性治疗策略。
