Hyperthermia Synergizes with Chemotherapy by Inhibiting PARP1-Dependent DNA Replication Arrest.
Cancer Res. 2016 May 15;76(10):2868-75. doi: 10.1158/0008-5472.CAN-15-2908. Epub 2016 Mar 24.
Schaaf L1, Schwab M2, Ulmer C3, Heine S1, Mürdter TE1, Schmid JO1, Sauer G4, Aulitzky WE5, van der Kuip H6.
Author information
• 1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany.
• 2Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany.
• 3Department of Surgery, Robert Bosch Hospital, Stuttgart, Germany.
• 4Department of Gynaecology, Robert Bosch Hospital, Stuttgart, Germany.
• 5Department of Oncology, Robert Bosch Hospital, Stuttgart, Germany.
• 6Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany. heiko.van-der-kuip@ikp-stuttgart.de.
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.
