Targeting the mutant PIK3CA gene by DNA-alkylating pyrrole-imidazole polyamide in cervical cancer.
Targeting the mutant PIK3CA gene by DNA-alkylating pyrrole-imidazole polyamide in cervical cancer.
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dna -烷基化吡咯-咪唑聚酰胺靶向PIK3CA突变基因治疗宫颈癌。
DOI：
10.1111/cas.14785
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发表时间：
2021-03
期刊：
影响因子：
5.7
通讯作者：
Nagase H
中科院分区：
文献类型：
--
作者：
Krishnamurthy S;Yoda H;Hiraoka K;Inoue T;Lin J;Shinozaki Y;Watanabe T;Koshikawa N;Takatori A;Nagase H
PIK 3CA是宫颈癌中最常突变的癌基因，PIK 3CA基因的体细胞突变导致PI 3 K活性增加。在宫颈癌中，PIK 3CA中的E545 K突变导致细胞增殖升高和细胞凋亡减少。在本研究中，我们设计并合成了一种新型的吡咯-咪唑聚酰胺-seco-CBI缀合物P3 AE 5 K，以靶向携带E545 K突变的PIK 3CA基因，通过核进入和吡咯-咪唑聚酰胺的独特序列特异性使其成为可能。P3 AE 5 K与含有E545 K突变的编码区的双链DNA相互作用。与传统的PI 3 K抑制剂相比，P3 AE 5 K在较低浓度下对E545 K阳性宫颈癌细胞表现出较强的细胞毒性。暴露于P3 AE 5 K的PIK 3CA突变体细胞表现出PIK 3CA mRNA和蛋白表达水平降低，以及随后的凋亡性细胞死亡。此外，P3 AE 5 K显著降低源自PIK 3CA突变细胞的小鼠异种移植模型中的肿瘤生长。总体而言，目前的数据强烈表明，烷基化吡咯-咪唑聚酰胺P3 AE 5 K应该是一种有前途的新候选药物，靶向宫颈癌中PIK 3CA的组成型激活突变。本研究提出了一种新的有前途的烷基化PI聚酰胺P3 AE 5 K，以靶向PIK 3CA中的E545 K突变。P3 AE 5 K对其靶核苷酸序列显示出高序列特异性结合亲和力，并在宫颈癌的小鼠异种移植肿瘤模型中下调突变体PIK 3CA表达并减少肿瘤生长。
PIK3CA is the most frequently mutated oncogene in cervical cancer, and somatic mutations in the PIK3CA gene result in increased activity of PI3K. In cervical cancer, the E545K mutation in PIK3CA leads to elevated cell proliferation and reduced apoptosis. In the present study, we designed and synthesized a novel pyrrole‐imidazole polyamide‐seco‐CBI conjugate, P3AE5K, to target the PIK3CA gene bearing the E545K mutation, rendered possible by nuclear access and the unique sequence specificity of pyrrole‐imidazole polyamides. P3AE5K interacted with double‐stranded DNA of the coding region containing the E545K mutation. When compared with conventional PI3K inhibitors, P3AE5K demonstrated strong cytotoxicity in E545K‐positive cervical cancer cells at lower concentrations. PIK3CA mutant cells exposed to P3AE5K exhibited reduced expression levels of PIK3CA mRNA and protein, and subsequent apoptotic cell death. Moreover, P3AE5K significantly decreased the tumor growth in mouse xenograft models derived from PIK3CA mutant cells. Overall, the present data strongly suggest that the alkylating pyrrole‐imidazole polyamide P3AE5K should be a promising new drug candidate targeting a constitutively activating mutation of PIK3CA in cervical cancer. The present study proposes a new promising alkylating PI polyamide, P3AE5K, to target the E545K mutation in PIK3CA. P3AE5K showed high sequence‐specific binding affinity to its target nucleotide sequence, and downregulated the mutant PIK3CA expression and reduced tumor growth in a mouse xenograft tumor model of cervical cancer.
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影响因子：
13.6
作者：
Fukuda, Noboru;Ueno, Takahiro;Serie, Kazuo
通讯作者：
Serie, Kazuo
影响因子：
--
作者：
Hou MM;Liu X;Wheler J;Naing A;Hong D;Coleman RL;Tsimberidou A;Janku F;Zinner R;Lu K;Kurzrock R;Fu S
通讯作者：
Fu S
影响因子：
5.7
作者：
Rozengurt E;Soares HP;Sinnet-Smith J
通讯作者：
Sinnet-Smith J
影响因子：
4.6
作者：
Mjos S;Werner HMJ;Birkeland E;Holst F;Berg A;Halle MK;Tangen IL;Kusonmano K;Mauland KK;Oyan AM;Kalland KH;Lewis AE;Mills GB;Krakstad C;Trovik J;Salvesen HB;Hoivik EA
通讯作者：
Hoivik EA
影响因子：
37.3
作者：
Henken FE;Banerjee NS;Snijders PJ;Meijer CJ;De-Castro Arce J;Rösl F;Broker TR;Chow LT;Steenbergen RD
通讯作者：
Steenbergen RD