Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide.
Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide.
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DOI：
10.1111/cas.12577
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发表时间：
2015-02
期刊：
影响因子：
5.7
通讯作者：
Maruyama T
中科院分区：
文献类型：
--
作者：
Ishima Y;Inoue A;Fang J;Kinoshita R;Ikeda M;Watanabe H;Maeda H;Otagiri M;Maruyama T
细胞自噬是引起耐药的主要原因之一。例如，血管生成抑制剂贝伐单抗仅显示出短暂和短期的治疗效果，而很少观察到长期的治疗益处，这可能是由于缺氧诱导的自噬。一氧化氮（NO）是一种具有多种功能的重要分子，最近有报道称其作为自噬的调节剂发挥作用。因此，通过NO克服耐药性的合理治疗策略将涉及将其直接递送至肿瘤。在这里，我们研究了一氧化氮对自噬的抑制作用，通过使用大分子NO供体S-亚硝化人血清白蛋白（SNO-HSA）具有高度的NO负载和肿瘤靶向潜力。在结肠26（C26）细胞中，SNO-HSA通过抑制JNK 1的磷酸化及其下游分子Beclin 1的表达，显著抑制缺氧诱导的自噬。SNO-HSA的作用也通过与Bev结合在体内得到证实。在携带C26的小鼠中，与SNO-HSA或贝伐单抗单独组相比，在组合组中实现了对肿瘤生长以及肺转移的显著抑制。与体外实验类似，肿瘤组织的免疫染色清楚地表明SNO-HSA抑制了贝伐珠单抗治疗诱导的肿瘤细胞自噬。除了SNO-HSA的其他已知的抗肿瘤作用，即诱导细胞凋亡和抑制多药外排泵，这些数据可能会打开癌症化疗的替代策略，利用SNO-HSA的能力，抑制自噬介导的耐药性，提高化疗的疗效。
Autophagy is one of the major causes of drug resistance. For example, the angiogenesis inhibitor bevacizumab shows only transient and short-term therapeutic effects, whereas long-term therapeutic benefits are rarely observed, probably due to hypoxia-induced autophagy. Nitric oxide (NO) is an important molecule with multiple functions, and it has recently been reported to function as a regulator of autophagy. Therefore, a reasonable therapeutic strategy for overcoming drug resistance by NO would involve it being directly delivered to the tumor. Here, we investigated the inhibitory effect of NO on autophagy by using a macromolecular NO donor S-nitrosated human serum albumin (SNO-HSA) with a high degree of NO loading and tumor targeting potential. In colon 26 (C26) cells, SNO-HSA significantly suppressed hypoxia-induced autophagy by inhibiting the phosphorylation of JNK1 and the expression of its downstream molecule Beclin1. The effect of SNO-HSA was also confirmed in vivo by combining it with Bev. In C26-bearing mice, significant suppression of tumor growth as well as lung metastasis was achieved in the combination group compared to the SNO-HSA or bevacizumab alone group. Similar to the in vitro experiments, the immunostaining of tumor tissues clearly showed that SNO-HSA inhibited the autophagy of tumor cells induced by bevacizumab treatment. In addition to other known antitumor effects of SNO-HSA, that is, the induction of apoptosis and the inhibition of multidrug efflux pumps, these data may open alternate strategies for cancer chemotherapy by taking advantage of the ability of SNO-HSA to suppress autophagy-mediated drug resistance and enhance the efficacy of chemotherapy.
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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：
3.2
作者：
Choudhari SK;Chaudhary M;Bagde S;Gadbail AR;Joshi V
通讯作者：
Joshi V
影响因子：
64.8
作者：
Sawyers, C
通讯作者：
Sawyers, C
影响因子：
78.5
作者：
Mathew, Robin;Karantza-Wadsworth, Vassiliki;White, Eileen
通讯作者：
White, Eileen
DOI：
10.1073/pnas.0502979102
发表时间：
2005-09-13
影响因子：
11.1
作者：
Ridnour, LA;Isenberg, JS;Wink, DA
通讯作者：
Wink, DA