Prevention of DMBA-induced mammary gland tumors in mice by a dual-function inhibitor of JAK3 and EGF receptor tyrosine kinases.
Prevention of DMBA-induced mammary gland tumors in mice by a dual-function inhibitor of JAK3 and EGF receptor tyrosine kinases.
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通过 JAK3 和 EGF 受体酪氨酸激酶双功能抑制剂预防 DMBA 诱导的小鼠乳腺肿瘤。
DOI：
10.1080/14728222.2020.1737014
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发表时间：
2020
影响因子：
5.8
通讯作者：
Uckun,FatihM
中科院分区：
文献类型：
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作者：
Sahin,Kazim;Yabas,Mehmet;Orhan,Cemal;Tuzcu,Mehmet;Sahin,TahaK;Ozercan,IbrahimH;Qazi,Sanjive;Uckun,FatihM
Objectives: We tested the chemopreventive effect of WHI-P131 in side by side evaluation with the standard anti-breast cancer drug paclitaxel in the well-established 7,12‐dimethylbenz(a)anthracene (DMBA)-induced breast cancer model.Methods: One hundred BALB/cmice were divided into five groups. (i) Control (ii) DMBA (iii) DMBA+ Paclitaxel (10 mg/kg) (iv) DMBA+WHI-P131 (Janex1, 50 mg/kg of BW, i.p, three times per week) (“J”) (v) DMBA+P+J. The duration of study was 25 weeks.Results: Our findings demonstrate that WHI-P131 impedes DMBA-induced carcinogenesis, reduces size, weight, and load of tumors (P< 0.001) in DMBA-challenged mice and improves their survival outcome (P< 0.01). The tumors developing despite WHI-P131 chemoprevention displayedattenuated levels of JAK3, STAT3, and NF-κB as well as increased I-κB expression (P< 0.001). Notably, these tumors exhibited significantly decreased levels of phosphorylated AKT-PI3-Kinase pathway signaling proteins p-mTOR, p-p70S6K1, and p-4E-BP1 (P< 0.001). Our findings are consistent with a model in which DMBA-induced malignant clones with low-level expression of the six signature proteins JAK3/STAT3/NF-κB/p-mTOR, p-p70S6K1/p-4E-BP1, albeit not as aggressive as their JAK3/STAT3/NF-κB overexpressing counterparts are capable of escaping chemo-preventive effects of WHI-P131.Conclusion: These insights may provide the foundation for new chemo-preventive strategies in which WHI-P131 is applied to prevent the development of aggressive forms of breast cancer.
