title: The Hsp70 inhibiting peptide aptamer A17 potentiates radiosensitization of tumor cells by Hsp90 inhibition.
abstract: The inhibition of heat shock protein 90 (Hsp90) is a promising strategy to increase the radiosensitivity of tumor cells. However, Hsp90 inhibition induces the expression of Hsp70 which is a prominent cytoprotective protein. Therefore, dual targeting of Hsp70 and Hsp90 might be beneficial to increase the radiosensitivity of tumor cells. Hsp70 inhibiting peptide aptamers have been shown to increase the sensitivity of tumor cells to apoptosis induced by different anticancer drugs. Herein, we studied the radiosensitizing activity of the Hsp70 inhibiting peptide aptamer A17 in combination with the Hsp90 inhibitor NVP-AUY922. Whereas A17 significantly increased apoptosis induction by NVP-AUY922 it did not significantly affect the radiosensitivity of human lung and breast cancer cells. However, Hsp70 inhibition by the aptamer A17 potentiated the radiosensitizing effects of the Hsp90 inhibitor NVP-AUY922. Mechanistically we speculate that an increased number of DNA double strand breaks and an enhanced G2/M arrest might be responsible for the increased radiosensitization in A17 expressing tumor cells. Therefore, the simultaneous inhibition of Hsp90 and Hsp70 combined with radiotherapy might provide a promising anti-cancer strategy.
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Institute of Innovative Radiotherapy (iRT), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Munich, Germany. Electronic address: daniela.schilling@tum.de.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schilling
authors.affiliation: INSERM UMR 866, Team Labeled LNCC, Faculty of Medicine, Dijon, France; Anticancer Center Georges François Leclerc (CGFL), Dijon, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Garrido
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Institute of Innovative Radiotherapy (iRT), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Munich, Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.affiliation: Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Institute of Innovative Radiotherapy (iRT), Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Munich, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D052158:Aptamers, Peptide / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D012118:Resorcinols / Q000494:pharmacology
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D052158:Aptamers, Peptide; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D011838:Radiation-Sensitizing Agents; D012118:Resorcinols
keywords: Aptamer; Heat shock protein 70 (Hsp70); Heat shock protein 90 (Hsp90); NVP-AUY922; Radiosensitization