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Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide.

ABSTRACT: 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.

SUBMITTER: Ishima Y

PROVIDER: S-EPMC4399024 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide.

Ishima Yu Y Inoue Aki A Fang Jun J Kinoshita Ryo R Ikeda Mayumi M Watanabe Hiroshi H Maeda Hiroshi H Otagiri Masaki M Maruyama Toru T

Cancer science 20150128 2

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 ...[more]

PMID: 25457681

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Project description:Nitric oxide (NO) releasing polymers have been widely applied as biomaterials for a variety of biomedical implants and devices. However, the chemical leaching of NO donors and their byproduct species is almost always observed during the application of polymers doped with NO donors, unless the donor is covalently linked to the polymer. Herein, we report the first NO releasing poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) fluorinated copolymer prepared by incorporating a fluorinated S-nitrosothiol as the NO donor. Under physiological conditions, the resulting polymeric films can release NO for 16?days. Importantly, due to both fluorine-fluorine and electrostatic charge interactions between the fluorinated NO donor and the PVDF-HFP copolymer, the total chemical leaching of the fluorinated NO donor and its disulfide product after 9?day was only 0.6% (mol%) of the initial amount of NO donor loaded into the film. These new NO release PVDF-HFP films exhibit antimicrobial and anti-biofilm activities against both Gram positive S. aureus and Gram negative P. aeruginosa strains. The NO-releasing PVDF-HFP polymer can also be coated on Teflon tubing to release NO under physiological conditions for extended time periods. This NO-releasing PVDF-HFP copolymer with greatly reduced chemical leaching could help enhance the biocompatibility and antimicrobial activity of various biomedical devices. STATEMENT OF SIGNIFICANCE: Fluoropolymers have been widely used in creating various biomedical implants and devices. However, nitric oxide (NO) release fluoropolymers have not been well studied to date. Additionally, in the application of biomaterials doped with NO donors, a significant amount of NO donors and their byproducts almost always leach into aqueous environment. We now report an NO releasing poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) fluoropolymer by incorporating a new fluorinated S-nitrosothiol. The NO release can last for 16?days under physiological conditions. The total chemical leaching was determined to be only 0.6?mol% of the initial S-nitrosothiol loaded. As expected, significant antimicrobial/anti-biofilm activities of the NO release PVDF-HFP film were observed against Gram positive S. aureus and Gram negative P. aeruginosa bacterial strains.

Dataset Information

Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide.

Publications

Poly-S-nitrosated human albumin enhances the antitumor and antimetastasis effect of bevacizumab, partly by inhibiting autophagy through the generation of nitric oxide.

Similar Datasets

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