Vasilcanu D, Weng W-H, Girnita A, Lui W-O, Vasilcanu R, Axelson M, Larsson O, Larsson C, Girnita L
Department of Oncology and Pathology, Karolinska University Hospital, Stockholm, Sweden.
Oncogene. 2006 May 25;25(22):3186-95. doi: 10.1038/sj.onc.1209339.
The cyclolignan PPP was recently demonstrated to inhibit the activity of insulin-like growth factor-1 receptor (IGF-1R), without affecting the highly homologous insulin receptor. In addition, PPP caused complete regression of xenografts derived from various types of cancer. These data highlight the use of this compound in cancer treatment. However, a general concern with antitumor agents is development of resistance. In light of this problem, we aimed to investigate whether malignant cells may develop serious resistance to PPP. After trying to select 10 malignant cell lines, with documented IGF-1R expression and apoptotic responsiveness to PPP treatment (IC50s less than 0.1 microM), only two survived an 80-week selection but could only tolerate maximal PPP doses of 0.2 and 0.5 microM, respectively. Any further increase in the PPP dose resulted in massive cell death. These two cell lines were demonstrated not to acquire any essential alteration in responsiveness to PPP regarding IGF-1-induced IGF-1R phosphorylation. Neither did they exhibit any increase in expression of the multidrug resistance proteins MDR1 or MRP1. Consistently, they did not exhibit decreased sensitivity to conventional cytostatic drugs. Rather, the sensitivity was increased. During the first half of the selection period, both cell lines responded with a temporary and moderate increase in IGF-1R expression, which appeared to be because of an increased transcription of the IGF-1R gene. This increase in IGF-1R might be necessary to make cells competent for further selection but only up to a PPP concentration of 0.2 and 0.5 microM. In conclusion, malignant cells develop no or remarkably weak resistance to the IGF-1R inhibitor PPP.
最近有研究表明，环木脂素PPP可抑制胰岛素样生长因子-1受体（IGF-1R）的活性，而不影响与之高度同源的胰岛素受体。此外，PPP可使源自各种癌症的异种移植瘤完全消退。这些数据凸显了该化合物在癌症治疗中的应用价值。然而，抗肿瘤药物普遍存在的一个问题是耐药性的产生。鉴于此问题，我们旨在研究恶性细胞是否会对PPP产生严重耐药性。在尝试筛选10种具有IGF-1R表达记录且对PPP治疗有凋亡反应（IC50小于0.1 microM）的恶性细胞系后，只有两种细胞系在80周的筛选后存活下来，但分别只能耐受最大剂量为0.2 microM和0.5 microM的PPP。PPP剂量的任何进一步增加都会导致大量细胞死亡。这两种细胞系在IGF-1诱导的IGF-1R磷酸化方面对PPP的反应性未出现任何本质改变。它们也未表现出多药耐药蛋白MDR1或MRP1的表达增加。一致的是，它们对传统细胞毒性药物的敏感性并未降低，反而有所增加。在筛选期的前半段，两种细胞系的IGF-1R表达均出现暂时且适度的增加，这似乎是由于IGF-1R基因转录增加所致。这种IGF-1R的增加可能是细胞能够进行进一步筛选所必需的，但仅在PPP浓度为0.2 microM和0.5 microM时如此。总之，恶性细胞对IGF-1R抑制剂PPP没有产生或仅产生非常微弱的耐药性。
