title: 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.
authors.affiliation: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Science, Kumamoto University, Kumamoto, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishima
authors.forename: Aki
authors.initials: A
authors.lastname: Inoue
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Ryo
authors.initials: R
authors.lastname: Kinoshita
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
authors.forename: Masaki
authors.initials: M
authors.lastname: Otagiri
authors.forename: Toru
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012709:Serum Albumin / Q000378:metabolism*; D000075462:Serum Albumin, Human
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D009603:Nitroso Compounds; C511514:S-nitrosoalbumin, human; D012709:Serum Albumin; D000068258:Bevacizumab; D009569:Nitric Oxide; D048055:Mitogen-Activated Protein Kinase 8; D000075462:Serum Albumin, Human
keywords: Autophagy; SNO-HSA; bevacizumab; drug resistance; nitric oxide