GSK690693作為pan-Akt抑制劑在腫瘤和神經(jīng)系統(tǒng)研究中的應(yīng)用

GSK690693（AbMole，M1789）是一種ATP競(jìng)爭(zhēng)性的泛Akt（pan-Akt）激酶抑制劑，通過(guò)特異性阻斷Akt信號(hào)軸發(fā)揮調(diào)控作用。GSK690693在胰腺癌來(lái)源異種移植（PDX）小鼠模型中，可使腫瘤體積減少至鹽水對(duì)照組的61%，并通過(guò)干擾Akt通路實(shí)現(xiàn)衰老-凋亡信號(hào)的轉(zhuǎn)換，顯著改善耐藥性[1]。GSK690693在結(jié)腸癌的研究中，與Irinotecan (CPT-11) 聯(lián)用可降低EVI1高表達(dá)細(xì)胞系的存活率，抑制腫瘤進(jìn)展[2]，相關(guān)實(shí)驗(yàn)采用2D/3D細(xì)胞模型（如HCT116等結(jié)腸癌細(xì)胞系）和異種移植小鼠模型[2]。

在神經(jīng)系統(tǒng)研究中，GSK690693（CAS No.：937174-76-0）表現(xiàn)出多重活性：在創(chuàng)傷后應(yīng)激障礙（PTSD）小鼠模型（C57BL/6品系）中，GSK690693能阻斷跑步機(jī)運(yùn)動(dòng)對(duì)海馬神經(jīng)發(fā)生和行為改善的促進(jìn)作用[3]。而在大鼠原代神經(jīng)元培養(yǎng)體系中，GSK690693能完全消除CXCL12誘導(dǎo)的膽堿能基因（CHT1、VAChT、ChAT）表達(dá)上調(diào)，并逆轉(zhuǎn)膽堿乙酰轉(zhuǎn)移酶活性和乙酰膽堿產(chǎn)量的增加[4]。GSK690693在骨癌痛模型（BCP，SD大鼠）中，通過(guò)抑制脊髓組織Akt蛋白磷酸化，降低WNK1表達(dá)，從而發(fā)揮緩解作用[5]。GSK690693（AbMole，M1789）在細(xì)胞凋亡調(diào)控中表現(xiàn)出多機(jī)制特性。

首先在橫紋肌肉瘤（RMS）細(xì)胞中，GSK690693與組蛋白去乙酰化酶抑制劑JNJ-26481585（Quisinostat） 協(xié)同增強(qiáng)caspase-9/-3的活化，該效應(yīng)可被BCL-2或MCL-1過(guò)表達(dá)所拮抗[6]。GSK690693在卵巢癌細(xì)胞系OVCAR3中，聯(lián)合miR-1284過(guò)表達(dá)可下調(diào)p-Akt和Bcl-2，同時(shí)上調(diào)Bax和caspase-3表達(dá)[7]。此外，在骨肉瘤143B細(xì)胞系及小鼠異種移植模型中，GSK690693通過(guò)抑制ZIP10-ITGA10-PI3K/AKT軸逆轉(zhuǎn)化療耐藥性[8]。在干細(xì)胞分化調(diào)控方面，GSK690693可阻斷STC2誘導(dǎo)的室管膜下區(qū)神經(jīng)前體細(xì)胞（NSPCs，來(lái)源于小鼠）的神經(jīng)元分化，而Akt激活劑SC79 能逆轉(zhuǎn)此效應(yīng)[9]。
*本文所述產(chǎn)品僅供科研使用

參考文獻(xiàn)及鳴謝
[1] Yang, D.; Zhang, Q.; Ma, Y.; et al. Augmenting the therapeutic efficacy of adenosine against pancreatic cancer by switching the Akt/p21-dependent senescence to apoptosis. EBioMedicine 2019, 47, 114-127.
[2] Pradeepa; Suresh, V.; Senapati, S.; et al. AKT inhibition sensitizes EVI1 expressing colon cancer cells to irinotecan therapy by regulating the Akt/mTOR axis. Cellular oncology (Dordrecht, Netherlands) 2022, 45 (4), 659-675.
[3] Sun, L.; Cui, K.; Xing, F.; et al. Akt dependent adult hippocampal neurogenesis regulates the behavioral improvement of treadmill running to mice model of post-traumatic stress disorder. Behavioural brain research 2020, 379, 112375.
[4] Yan, J.; Zhao, W.; Guo, M.; et al. CXCL12 Regulates the Cholinergic Locus and CHT1 Through Akt Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2016, 40 (5), 982-992.
[5] Fu, X.; Zhang, Y.; Zhang, R. Regulatory role of PI3K/Akt/WNK1 signal pathway in mouse model of bone cancer pain. Scientific reports 2023, 13 (1), 14321.
[6] Haydn, T.; Metzger, E.; Schuele, R.; et al. Concomitant epigenetic targeting of LSD1 and HDAC synergistically induces mitochondrial apoptosis in rhabdomyosarcoma cells. Cell death & disease 2017, 8 (6), e2879.
[7] Pan, C.; Wang, D.; Zhang, Y.; et al. MicroRNA-1284 Inhibits Cell Viability and Induces Apoptosis of Ovarian Cancer Cell Line OVCAR3. Oncology research 2016, 24 (6), 429-435.
[8] Li, H.; Shen, X.; Ma, M.; et al. ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway. Journal of experimental & clinical cancer research : CR 2021, 40 (1), 340.
[9] Guo, Z.; Zhang, H.; Jingele, X.; et al. Stanniocalcin 2 Promotes Neuronal Differentiation in Neural Stem/Progenitor Cells of the Mouse Subventricular Zone Through Activation of AKT Pathway. Stem cells and development 2024, 33 (19-20), 551-561