Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis and cooperate with cytotoxic drugs in human cancer cell lines
Antisense oligonucleotides targeting the epidermal growth factor receptor inhibit proliferation, induce apoptosis and cooperate with cytotoxic drugs in human cancer cell lines
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DOI：
10.1002/ijc.1335
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发表时间：
2001-07-15
影响因子：
6.4
通讯作者：
Tortora, G
中科院分区：
文献类型：
--
作者：
Ciardiello, F;Caputo, R;Tortora, G
我们构建了一系列针对人类 (EGFR) mRNA 不同区域的 22 个硫代磷酸酯 20 聚体反义寡核苷酸，用 EGFR 反义寡核苷酸处理显示出对软琼脂中人 GEO 结肠癌细胞生长的剂量依赖性抑制，蛋白质印迹分析表明用每种 EGFR 反义寡核苷酸处理后 EGFR 表达显着降低。然而，EGFR 反义序列抑制 GEO 锚定非依赖性生长的能力各不相同，IC50 范围在 0.5 至 3.5 μM 之间。其中两种针对人类 EGFR mRNA 2457-2476 和 614-4633 碱基之间区域的反义寡核苷酸已被修饰为杂合 DNA/RNA 混合主链寡核苷酸 (MBO)，以检查其体内抗癌特性。这两种EGFR反义MBO保留了与针对相同EGFR mRNA序列的完全硫代磷酸酯EGFR反义寡核苷酸相同的生物学特性，例如阻断EGFR合成、抑制细胞生长和增强表达功能性EGFR的人类癌细胞系的程序性细胞死亡。此外，在用这些EGFR反义MBO与细胞毒性药物（包括顺铂）联合治疗后，观察到对CEO癌细胞的生长抑制作用增强。阿霉素、紫杉醇或托泊替康，这些结果显示了特定 EGFR 反义寡核苷酸的抗增殖活性，并允许鉴定新型 EGFR 反义 MBO，值得进一步评估，作为单独或与表达功能性 EGFR 的人类癌症中的细胞毒性药物组合的潜在选择性抗癌药物。 (C) 2001 Wiley-Liss, Inc.
We have constructed a series of 22 phosphorothioate 20-mer antisense oligonucleotides directed against different regions of the human (EGFR) mRNA, Treatment with EGFR antisense oligonucleotides showed a dose-dependent inhibition of human GEO colon cancer cell growth in soft agar, Western blot analysis demonstrated a significant reduction in EGFR expression after treatment with each EGFR antisense oligonucleotide. The ability to inhibit GEO anchorage-independent growth, however, varied among the EGFR antisense sequences with an IC50 ranging between 0.5 and 3.5 muM. Two of these antisense oligonucleotides targeting the regions between 2457-2476 and 614-4633 bases of the human EGFR mRNA have been modified as hybrid DNA/RNA mixed backbone oligonucleotides (MBO) to examine their anticancer properties in vivo. The 2 EGFR antisense MBOs retained the same biological properties of the fully phosphorothioate EGFR antisense oligonucleotides targeting the same EGFR mRNA sequences, such as blocking EGFR synthesis, inhibiting cell growth and enhancing programmed cell death in human cancer cell lines that express functional EGFRs, Furthermore, a potentiation in the growth inhibitory effect on CEO cancer cells was observed after treatment with these EGFR antisense MBOs in combination with cytotoxic drugs, including cisplatin, doxorubicin, paclitaxel, or topotecan, These results show the antiproliferative activity of specific EGFR antisense oligonucleotides and allow to identify novel EGFR antisense MBOs that deserve further evaluation as potential selective anticancer agents alone or in combination with cytotoxic drugs in human carcinomas that express functional EGFRs. (C) 2001 Wiley-Liss, Inc.