Novel poly (ADP-ribose) polymerase inhibitor, AZD2281, enhances radiosensitivity of both normoxic and hypoxic esophageal squamous cancer cells

Abstract

Radiotherapy plays an important role in the treatment of esophageal squamous cell carcinoma (ESCC). However, the outcome of radiotherapy in ESCC remains unsatisfactory because esophageal squamous cancer cells, particularly those under hypoxic condition, exhibit radioresistance. The aim of this study was to determine whether or not AZD2281, a potent poly (ADP-ribose) polymerase (PARP) inhibitor, could enhance the radiation sensitivity of two ESCC cell lines, namely ECA109 and TE13. The radiosensitizing effect of AZD2281 was evaluated on the basis of cell death, clonogenic survival and tumor xenograft progression. AZD2281 alone was slightly toxic to ESCC cell lines. Apoptosis was increased and clonogenic survival was decreased in both cell lines when AZD2281 was combined with ionizing radiation (IR) under normoxic condition. AZD2281 enhanced IR-induced apoptosis to a more significant level under chronic hypoxic condition (0.2% O(2), 48 hour) than under normoxic condition. AZD2281 also slightly enhanced clonogenic cell death under chronic hypoxic condition compared with that under normoxic condition. This result could be associated with increased radiation-induced DNA double-strand breaks (DSB), decreased DSB repair and increased apoptosis of ESCC cells. Furthermore, homologous recombination (HR) protein Rad51 expression and focus formation were decreased in ESCC cells exposed to moderate chronic hypoxic condition (0.2% O(2), 48 hour); this result indicated that chronic hypoxic ESCC cells were HR deficient, possibly causing contextual synthetic lethality with PARP inhibitor in radiation sensitization. AZD2281 was also a radiation sensitizer in ESCC tumor xenograft models. Hence, in vitro and in vivo findings provide evidence that AZD2281 potently sensitizes ESCC cells to X-ray irradiation. The selective cell killing of HR-defective hypoxic cells contributes to radiosensitization by PARP inhibitor in ESCC cells under hypoxic condition.

Hypoxia Potentiates the Radiation-Sensitizing Effect of Olaparib in Human Non-Small Cell Lung Cancer Xenografts by Contextual Synthetic Lethality

“…Our observation that olaparib exhibited greater radiation-sensitizing effect under hypoxia than under normoxia in vitro is in agreement with others' finding (35) . However, no evidence of radiosensitization was observed for nonhypoxic tumor cells in vivo.…”

mRNA and methylation profiling of radioresistant esophageal cancer cells: the involvement of Sall2 in acquired aggressive phenotypes

“…However, tumors treated with fractionated doses of ionizing radiation (IR) often acquire radioresistance 7, which has emerging as an important factor in restricting the efficacy of radiotherapy for ESCC patients. Mechanisms to explain radiation resistance include cancer stem cells (CSCs) 8,9, DNA damage repair systems 10, hypoxia 11, anti-apoptotic capability 12, Wnt/β-catenin 13, mTOR 14 and histone modifications 7. However, reports describing key molecules driving radiation resistance are still limited.…”

In vivo studies of the PARP inhibitor, AZD-2281, in combination with fractionated radiotherapy: An exploration of the therapeutic ratio

“…AZD2281 is a compound that is an inhibitor of the mammalian PARP-1 enzyme. It has been shown to kill selected tumor cell lines in vitro and inhibit xenograft growth in vivo either as a stand-alone treatment in tumors that have germline or somatic defects in DNA repair genes or in combination with chemotherapy or radiotherapy [12][13][14]. In addition to inherent genetics, tumor cells may also be preferentially sensitized by PARP inhibitors (PARPi) to radiotherapy by targeting of the endothelium and tumor vasculature, and increased sensitivity of repair-deficient hypoxic cells (reviewed in [10]).…”