Abstract 3630: Inhibition of PARP by hyperthermia or pharmacological inhibitors synergize with cisplatin and doxorubicin but not with 5-FU or paclitaxel

Abstract

Abstract Short-term, high-dose chemotherapy together with hyperthermia (HIPEC) is widely used for treatment of peritoneal carcinomatosis. However, it is fairly known which agents currently used for HIPEC actually act synergistically with elevated temperature. Furthermore, the molecular mechanisms behind the potentiating effects are incompletely understood. To mirror the clinical HIPEC setting we cultivated 2 ovarian and 2 colon cancer cell lines under hypoxic conditions and performed a 1-hour treatment at atmospheric oxygen levels with Cisplatin, Doxorubicin, 5FU, or Paclitaxel at either 37°C or 42°C. Cells were then evaluated for long-term survival, DNA strand break repair, poly(ADP-Ribosy)lation, and γH2AX and P-53BP1 foci formation. Importantly, we found that Cisplatin as well as Doxorubicin were potentiated by hyperthermia as revealed by a significantly reduced colony forming ability whereas high temperature had no effects together with 5FU or Paclitaxel on long-term survival. The synergistic effects on survival were due to compromised DNA strand break repair capacity and followed by a significantly enhanced number of double strand breaks. Interestingly, this was paralleled by a diminished poly(ADP-Ribosy)lation indicating a reduced activity of PARP. The role of this enzyme for the hyperthermia effects was confirmed by using clinically relevant PARP inhibitors. Combination of PARP inhibitors was synergistic with the same subset of compounds as observed with hyperthermia. Short-term treatment with PARP inhibitors mimicked the effects of elevated temperature both on survival and DNA repair capacity. Hyperthermia and PARP inhibitors also led to a comparable increase of γH2AX and P-53BP1 foci in cells treated with Doxorubicin or Cisplatin. In conclusion our data indicate that the cytotoxic effects of only a subset of currently used chemotherapeutics can be potentiated by hyperthermia. The molecular mechanisms behind these synergistic effects are related to PARP functions in DNA repair. Citation Format: Lea Schaaf, Christoph Ulmer, Wolfgang Steurer, Thomas E. Mürdter, Walter E. Aulitzky, Heiko van der Kuip. Inhibition of PARP by hyperthermia or pharmacological inhibitors synergize with cisplatin and doxorubicin but not with 5-FU or paclitaxel. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3630. doi:10.1158/1538-7445.AM2015-3630