Combined efficacy of cediranib and quinacrine in glioma is enhanced by hypoxia and causally linked to autophagic vacuole accumulation.
Combined efficacy of cediranib and quinacrine in glioma is enhanced by hypoxia and causally linked to autophagic vacuole accumulation.
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DOI：
10.1371/journal.pone.0114110
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Pike MM
中科院分区：
文献类型：
--
作者：
Lobo MR;Wang X;Gillespie GY;Woltjer RL;Pike MM
我们之前曾报道，抗血管生成受体酪氨酸激酶抑制剂西地尼布与后期自噬抑制剂奎纳克林联合使用，可显着增强其体内抗神经胶质瘤功效。目前的研究探讨了缺氧和自噬在西地尼布/奎纳克林联合疗效中的作用。 EF5 免疫染色显示小鼠颅内 4C8 神经胶质瘤普遍缺氧，与高级别神经胶质瘤一致。使用 4C8 神经胶质瘤细胞进行的 MTS 细胞活力测定显示，缺氧增强了西地尼布/奎纳克林联合用药的功效：1 µM 西地尼布 +2.5 µM 奎纳克林诱导的细胞活力降低分别为 78±7%（缺氧）与 31±3%（常氧），p<0.05。与所有其他组相比，西地尼布/奎纳克林/缺氧组的细胞凋亡显着增加。自噬液泡生物标志物 LC3-II 因西地尼布、奎纳克林或缺氧而急剧增加。西地尼布/奎纳克林联合用药进一步增加了 LC3-II，其中西地尼布/奎纳克林/缺氧联合用药的增加幅度最大。早期自噬抑制剂 3-MA 联合西地尼布/奎纳克林/缺氧可防止 LC3-II 积聚，并显着减弱相关的细胞活力下降。西地尼布与另一种晚期自噬抑制剂巴弗洛霉素 A1 的联合疗效是相加的，但缺乏缺氧的实质性增强作用。与奎纳克林相比，巴弗洛霉素 A1 的 LC3-II 积累显着降低。西地尼布和奎纳克林均强烈抑制 Akt 磷酸化，而巴弗洛霉素 A1 没有作用。我们的结果提供了令人信服的证据，表明自噬液泡积累在西地尼布/奎纳克林组合的抗神经胶质瘤细胞毒性功效中起着因果作用。这种积累可能与神经胶质瘤肿瘤微环境中普遍存在的缺氧刺激自噬体诱导以及西地尼布和奎纳克林的 Akt 信号传导抑制有关。奎纳克林抑制 Akt 和自噬泡降解的独特能力可能会增强其驱动细胞毒性自噬泡积累的能力。这些发现为西地尼布/奎纳克林联合治疗恶性胶质瘤的临床评估提供了理论依据。
We have previously reported that the in vivo anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib is substantially enhanced via combination with the late-stage autophagy inhibitor quinacrine. The current study investigates the role of hypoxia and autophagy in combined cediranib/quinacrine efficacy. EF5 immunostaining revealed a prevalence of hypoxia in mouse intracranial 4C8 glioma, consistent with high-grade glioma. MTS cell viability assays using 4C8 glioma cells revealed that hypoxia potentiated the efficacy of combined cediranib/quinacrine: cell viability reductions induced by 1 µM cediranib +2.5 µM quinacrine were 78±7% (hypoxia) vs. 31±3% (normoxia), p<0.05. Apoptosis was markedly increased for cediranib/quinacrine/hypoxia versus all other groups. Autophagic vacuole biomarker LC3-II increased robustly in response to cediranib, quinacrine, or hypoxia. Combined cediranib/quinacrine increased LC3-II further, with the largest increases occurring with combined cediranib/quinacrine/hypoxia. Early stage autophagy inhibitor 3-MA prevented LC3-II accumulation with combined cediranib/quinacrine/hypoxia and substantially attenuated the associated reduction in cell viability. Combined efficacy of cediranib with bafilomycin A1, another late-stage autophagy inhibitor, was additive but lacked substantial potentiation by hypoxia. Substantially lower LC3-II accumulation was observed with bafilomycin A1 in comparison to quinacrine. Cediranib and quinacrine each strongly inhibited Akt phosphoryation, while bafilomycin A1 had no effect. Our results provide compelling evidence that autophagic vacuole accumulation plays a causal role in the anti-glioma cytotoxic efficacy of combined cediranib/quinacrine. Such accumulation is likely related to stimulation of autophagosome induction by hypoxia, which is prevalent in the glioma tumor microenvironment, as well as Akt signaling inhibition from both cediranib and quinacrine. Quinacrine's unique ability to inhibit both Akt and autophagic vacuole degradation may enhance its ability to drive cytotoxic autophagic vacuole accumulation. These findings provide a rationale for a clinical evaluation of combined cediranib/quinacrine therapy for malignant glioma.
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影响因子：
11.2
作者：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
通讯作者：
Aghi MK
影响因子：
7.8
作者：
Degtyarev, Michael;De Maziere, Ann;Orr, Christine;Lin, Jie;Lee, Brian B.;Tien, Janet Y.;Prior, Wei W.;van Dijk, Suzanne;Wu, Hong;Gray, Daniel C.;Davis, David P.;Stern, Howard M.;Murray, Lesley J.;Hoeflich, Klaus P.;Klumperman, Judith;Friedman, Lori S.;Lin, Kui
通讯作者：
Lin, Kui
DOI：
10.1186/1478-811x-9-13
发表时间：
2011-05-15
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Ehsanian R;Van Waes C;Feller SM
通讯作者：
Feller SM
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
DOI：
10.1038/nrc2442
发表时间：
2008-08
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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