G-quartet oligonucleotides: A new class of signal transducer and activator of transcription 3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis
G-quartet oligonucleotides: A new class of signal transducer and activator of transcription 3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis
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DOI：
10.1158/0008-5472.can-03-4041
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Tweardy, DJ
中科院分区：
文献类型：
--
作者：
Jing, NJ;Li, YD;Tweardy, DJ
Stat3 是一种信号分子和癌基因，在许多人类恶性肿瘤中频繁激活，包括大多数前列腺癌、乳腺癌和头颈癌；然而，目前还没有专门针对 Stat3 的化疗方法应用于临床。我们最近开发了富含 G 的寡脱氧核苷酸，它形成分子内 G 四联体结构 (GQ-ODN)，作为一类新型 Stat3 抑制剂。 GQ-ODN 靶向 Stat3 蛋白，直接抑制其结合 DNA 的能力。当使用聚乙烯亚胺作为载体递送到细胞中时，GQ-ODN 阻断配体诱导的 Stat3 激活和 Stat3 介导的抗凋亡基因转录。为了确定 GQ-ODN 作为潜在的新型化疗药物的有效性，我们通过尾静脉注射将 GQ-ODN（T40214 或 T40231）加聚乙烯亚胺或单独的聚乙烯亚胺（安慰剂）全身注射到前列腺和乳腺肿瘤异种移植物的裸鼠中。尽管安慰剂治疗的小鼠中乳腺肿瘤异种移植物的平均体积在 18 天内增加了 7 倍以上，但 GQ-ODN 治疗的小鼠中的异种移植物保持不变。同样，安慰剂治疗的小鼠中前列腺肿瘤异种移植物的平均体积在 10 天内增加了 9 倍，而 GQ-ODN 治疗的小鼠中的异种移植物仅增加了 2 倍。对 GQ-ODN 治疗小鼠肿瘤的生化检查表明，与安慰剂治疗小鼠的肿瘤相比，Stat3 激活、抗凋亡蛋白 Bcl-2 和 Bcl-x(L) 水平显着降低，凋亡细胞数量增加 8 倍。因此，靶向 Stat3 的 GQ-ODN 在递送到肿瘤异种移植物中时会诱导肿瘤细胞凋亡，代表了一类新型化疗药物，有望用于多种形式的转移性癌症的全身治疗。
Stat3 is a signaling molecular and oncogene activated frequently in many human malignancies including the majority of prostate, breast, and head and neck cancers; yet, no current chemotherapeutic approach has been implemented clinically that specifically targets Stat3. We recently developed G-rich oligodeoxynucleotides, which form intramolecular G-quartet structures (GQ-ODN), as a new class of Stat3 inhibitor. GQ-ODN targeted Stat3 protein directly inhibiting its ability to bind DNA. When delivered into cells using polyethyleneimine as vehicle, GQ-ODN blocked ligand-induced Stat3 activation and Stat3-mediated transcription of antiapoptotic genes. To establish the effectiveness of GQ-ODN as a potential new chemotherapeutic agent, we systemically administered GQ-ODN (T40214 or T40231) plus polyethyleneimine or polyethyleneimine alone (placebo) by tail-vein injection into nude mice with prostate and breast tumor xenografts. Whereas the mean volume of breast tumor xenografts in placebo-treated mice increased >7-fold over 18 days, xenografts in the GQ-ODN-treated mice remained unchanged. Similarly, whereas the mean volume of prostate tumor xenografts in placebo-treated mice increased 9-fold over 10 days, xenografts in GQ-ODN-treated mice increased by only 2-fold. Biochemical examination of tumors from GQ-ODN-treated mice demonstrated a significant reduction in Stat3 activation, levels of the antiapoptotic proteins Bcl-2 and Bcl-x(L), and an 8-fold increase in the number of apoptotic cells compared with the tumors of placebo-treated mice. Thus, GQ-ODN targeting Stat3 induces tumor cell apoptosis when delivered into tumor xenografts and represents a novel class of chemotherapeutic agents that holds promise for the systemic treatment of many forms of metastatic cancer.