Cytotoxic and Antitumor Activity of Lactaptin in Combination with Autophagy Inducers and Inhibitors.
Autophagy is a degradative process in which cellular organelles and proteins are recycled to restore homeostasis and cellular metabolism. Autophagy can be either a prosurvival or a prodeath process and remains one of the most fundamental processes for cell vitality. Thus autophagy modulation is an i...
| Publicado en: | BioMed Research International pp. 1 - 17 |
|---|---|
| Autores principales: | , , , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
6/17/2019
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=137023164&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 137023164 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 23146133 FT2T jtl: BioMed Research International issn: 23146133 maglogo: N pubinfo: dt: 6/17/2019 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 137023164 137023164 137023164 10.1155/2019/4087160 137023164 ppf: 1 ppct: 16 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Cytotoxic and Antitumor Activity of Lactaptin in Combination with Autophagy Inducers and Inhibitors. aug: au: Bagamanshina, Anastasia V. Troitskaya, Olga S. Nushtaeva, Anna A. Yunusova, Anastasia Yu Starykovych, Marina O. Kuligina, Elena V. Kit, Yuri Ya Richter, Max Wohlfromm, Fabian Kähne, Thilo Lavrik, Inna N. Richter, Vladimir A. Koval, Olga A. affil: Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Lavrentiev Ave. 8, 630090 Novosibirsk, Russia sug: subj: Milk Proteins Pharmacodynamics Drug Synergism Chloroquine Pharmacodynamics Protein Kinase Inhibitors Pharmacodynamics Sirolimus Pharmacodynamics Cell Line, Tumor Drug Effects Cell Death Drug Effects Autophagy Drug Effects Animal Studies Mice Blotting, Western Microscopy, Electron Reactive Oxygen Species Drug Effects Autophagy-Related Proteins Drug Effects Nerve Tissue Proteins Drug Effects Carrier Proteins Drug Effects Peptide Hydrolases Drug Effects ab: Autophagy is a degradative process in which cellular organelles and proteins are recycled to restore homeostasis and cellular metabolism. Autophagy can be either a prosurvival or a prodeath process and remains one of the most fundamental processes for cell vitality. Thus autophagy modulation is an important approach for reinforcement anticancer therapeutics. Earlier we have demonstrated that recombinant analog of human milk protein lactaptin (RL2) induced apoptosis of various cultured cancer cells and activated lipidation of microtubule-associated protein 1 light chain 3 (LC3). In this study we investigated whether autophagy inhibitors—chloroquine (CQ), Ku55933 (Ku), and 3-methyladenine (3MA)—or inducer—rapamycin (Rap)—can enhance cytotoxic activity of lactaptin analog in cancer cells and its anticancer activity in the mice model. Western Blot analysis revealed that RL2 induced short-term autophagy in MDA-MB-231 and MCF-7 cells at early stages of incubation and that these data were confirmed by the transmission electron microscopy of autophagosome/autophagolysosome formation. RL2 stimulates reactive oxygen species (ROS) production, autophagosomes accumulation, upregulation of ATG5 with processing of LC3I to LC3II, and downregulation of p62/sequestosome 1 (p62). We have shown that autophagy modulators, CQ, Ku, and Rap, synergistically increased cytotoxicity of RL2, and RL2 with CQ induced autophagic cell death. In addition, CQ, Ku, and Rap in combination with RL2 decreased activity of lysosomal protease Cathepsin D. More importantly, combining RL2 with CQ, we improved antitumor effect in mice. Detected synergistic cytotoxic effects of both types of autophagy regulators, inhibitors, and inducers with RL2 against cancer cells allow us to believe that these combinations can be a basis for the new anticancer approach. Finally, we suppose that CQ and Rap promoting of short-term RL2-induced autophagy interlinks with final autophagic cell death. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|