Abstract Title:

Hyperthermia synergizes with chemotherapy by inhibiting PARP1-dependent DNA replication arrest.

Abstract Source:

Cancer Res. 2016 Mar 24. Epub 2016 Mar 24. PMID: 27013194

Abstract Author(s):

Lea Schaaf, Matthias Schwab, Christoph Ulmer, Simon Heine, Thomas E Mürdter, Jens O Schmid, Georg Sauer, Walter E Aulitzky, Heiko van der Kuip

Article Affiliation:

Lea Schaaf


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 if 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. Further, hyperthermia blocked this histone modification as efficiently as pharmacological inhibitors of polyADP-ribosyl polymerase (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 slowings. Overall, our work reveals how PARP blockade - either by hyperthermia or small molecule inhibition - can increase chemotherapy-induced damage in BRCA-competent cells.

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