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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Combined Modality Therapy
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • DNA Replication*
  • Doxorubicin / pharmacology*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Hyperthermia, Induced*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / therapy*
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / pathology
  • Peritoneal Neoplasms / therapy
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured


  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • RNA, Messenger
  • Doxorubicin
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Cisplatin