Combination of AZD3463 and DZNep Prevents Bone Metastasis of Breast Cancer by Suppressing Akt Signaling.
Combination of AZD3463 and DZNep Prevents Bone Metastasis of Breast Cancer by Suppressing Akt Signaling.
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AZD3463 和 DZNep 组合通过抑制 Akt 信号传导预防乳腺癌骨转移
DOI：
10.3389/fphar.2021.652071
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发表时间：
2021
影响因子：
5.6
通讯作者：
Qin A
中科院分区：
文献类型：
--
作者：
He W;Cao X;Rong K;Chen X;Han S;Qin A
破骨细胞过度激活导致的骨质溶解是乳腺癌骨转移的严重并发症之一。先前的研究报道抗癌药物DZNep通过激活Akt信号通路诱导癌细胞凋亡。然而，DZNep对乳腺癌骨转移的影响尚不清楚。我们先前发现DZNep通过激活Akt增强破骨细胞分化。因此，我们探索了将抗癌药物AZD3463（一种Akt抑制剂）与DZNep联合使用，因为AZD3463既能作为抗癌药物，又有可能改善骨质侵蚀。我们通过用DZNep和AZD3463处理细胞，在体外评估了破骨细胞和乳腺癌细胞的表型以及Akt信号通路。此外，我们在小鼠胫骨中建立了乳腺癌骨转移动物模型，以进一步确定它们在体内的联合作用。单独用DZNep处理破骨细胞前体细胞会增加破骨细胞分化、骨吸收以及破骨细胞特异性基因的表达。这些作用被AZD3463改善。DZNep和AZD3463的组合抑制了乳腺癌细胞的增殖、集落形成、迁移和侵袭。最后，腹腔注射DZNep和AZD3463改善了肿瘤进展并防止了骨质流失。总之，DZNep与AZD3463联合通过抑制Akt信号通路预防了骨骼并发症并抑制了乳腺癌进展。
Osteolysis resulting from osteoclast overactivation is one of the severe complications of breast cancer metastasis to the bone. Previous studies reported that the anti-cancer agent DZNep induces cancer cell apoptosis by activating Akt signaling. However, the effect of DZNep on breast cancer bone metastasis is unknown. We previously found that DZNep enhances osteoclast differentiation by activating Akt. Therefore, we explored the use of the anti-cancer agent AZD3463 (an Akt inhibitor) along with DZNep, as AZD3463 can act as an anti-cancer agent and can also potentially ameliorate bone erosion. We evaluated osteoclast and breast cancer cell phenotypes and Akt signaling in vitro by treating cells with DZNep and AZD3463. Furthermore, we developed a breast cancer bone metastasis animal model in mouse tibiae to further determine their combined effects in vivo. Treatment of osteoclast precursor cells with DZNep alone increased osteoclast differentiation, bone resorption, and expression of osteoclast-specific genes. These effects were ameliorated by AZD3463. The combination of DZNep and AZD3463 inhibited breast cancer cell proliferation, colony formation, migration, and invasion. Finally, intraperitoneal injection of DZNep and AZD3463 ameliorated tumor progression and protected against bone loss. In summary, DZNep combined with AZD3463 prevented skeletal complications and inhibited breast cancer progression by suppressing Akt signaling.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1016/j.bbrc.2020.10.058
发表时间：
2020-12-17
影响因子：
3.1
作者：
Bagca, Bakiye Goker;Ozates, Neslihan Pinar;Avci, Cigir Biray
通讯作者：
Avci, Cigir Biray
影响因子：
4.8
作者：
Li, XT;Udagawa, N;Takahashi, N
通讯作者：
Takahashi, N
影响因子：
4.8
作者：
Hortobagyi, Gabriel N.
通讯作者：
Hortobagyi, Gabriel N.
影响因子：
3.1
作者：
Jensen, Anders Bonde;Wynne, Christopher;Lombardi, Antonio
通讯作者：
Lombardi, Antonio