title: Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest.
abstract: Although hyperthermia offers clinical appeal to sensitize cells to chemotherapy, this approach has been limited in terms of long-term outcome as well as economic and technical burden. Thus, a more detailed knowledge about how hyperthermia exerts its effects on chemotherapy may illuminate ways to improve the approach. Here, we asked whether hyperthermia alters the response to chemotherapy-induced DNA damage and whether this mechanism is involved in its sensitizing effect in BRCA-competent models of ovarian and colon cancer. Notably, we found that hyperthermia delayed the repair of DNA damage caused by cisplatin or doxorubicin, acting upstream of different repair pathways to block histone polyADP-ribosylation (PARylation), a known effect of chemotherapy. Furthermore, hyperthermia blocked this histone modification as efficiently as pharmacologic inhibitors of PARP (PARPi), producing comparable delay in DNA repair, induction of double-strand breaks (DSB), and cell cytotoxicity after chemotherapy. Mechanistic investigations indicated that inhibiting PARylation by either hyperthermia or PARPi induced lethal DSB upon chemotherapy treatment not only by reducing DNA repair but also by preventing replication fork slowing. Overall, our work reveals how PARP blockade, either by hyperthermia or small-molecule inhibition, can increase chemotherapy-induced damage in BRCA-competent cells. Cancer Res; 76(10); 2868-75. ©2016 AACR.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Schaaf
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ulmer
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Heine
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mürdter
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
authors.forename: Jens O
authors.initials: JO
authors.lastname: Schmid
authors.affiliation: Department of Gynaecology, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Sauer
authors.affiliation: Department of Oncology, Robert Bosch Hospital, Stuttgart, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Aulitzky
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. heiko.van-der-kuip@ikp-stuttgart.de.
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D006979:Hyperthermia, Induced; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D004317:Doxorubicin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D002945:Cisplatin