Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib.
Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown to mediate development of resistance. In this study we systematically screened a library of 306 known anti-cancer drugs for their ability to induce autophagy using a cell-based assay. 11...
| Publicado en: | Cancer Letters Vol. 435; pp. 32 - 44 |
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| Autores principales: | , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Elsevier B.V.
Oct2018
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| 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=131402485&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 131402485 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 03043835 3J8 jtl: Cancer Letters issn: 03043835 maglogo: N pubinfo: dt: Oct2018 vid: 435 pid: 1004 pub: Elsevier B.V. artinfo: ui: 131402485 131402485 NLM30055290 131402485 10.1016/j.canlet.2018.07.028 NLM30055290 131402485 ppf: 32 ppct: 12 formats: tig: atl: Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib. aug: au: Dyczynski, Matheus Yu, Yasmin Otrocka, Magdalena Parpal, Santiago Braga, Tiago Henley, Aine Brigette Zazzi, Henric Lerner, Mikael Wennerberg, Krister Viklund, Jenny Martinsson, Jessica Grandér, Dan De Milito, Angelo Pokrovskaja Tamm, Katja affil: Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden sug: subj: Autophagy Drug Effects Laboratory Chemicals Pharmacodynamics Breast Neoplasms Drug Therapy Phosphotransferases Antagonists and Inhibitors Breast Neoplasms Metabolism Phosphotransferases Metabolism Human Mice Protein Kinase Inhibitors Pharmacodynamics Cell Line, Tumor Drug Screening Assays, Antitumor Methods Cell Physiology Drug Effects Apoptosis Drug Effects Animal Studies Breast Neoplasms Pathology Validation Studies Comparative Studies Evaluation Research Multicenter Studies ab: Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown to mediate development of resistance. In this study we systematically screened a library of 306 known anti-cancer drugs for their ability to induce autophagy using a cell-based assay. 114 of the drugs were classified as autophagy inducers; for 16 drugs, the cytotoxicity was potentiated by siRNA-mediated knock-down of Atg7 and Vps34. These drugs were further evaluated in breast cancer cell lines for autophagy induction, and two tyrosine kinase inhibitors, Sunitinib and Erlotinib, were selected for further studies. For the pharmacological inhibition of autophagy, we have characterized here a novel highly potent selective inhibitor of Vps34, SB02024. SB02024 blocked autophagy in vitro and reduced xenograft growth of two breast cancer cell lines, MDA-MB-231 and MCF-7, in vivo. Vps34 inhibitor significantly potentiated cytotoxicity of Sunitinib and Erlotinib in MCF-7 and MDA-MB-231 in vitro in monolayer cultures and when grown as multicellular spheroids. Our data suggests that inhibition of autophagy significantly improves sensitivity to Sunitinib and Erlotinib and that Vps34 is a promising therapeutic target for combination strategies in breast cancer. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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