PARP inhibitor Olaparib increases the sensitization to radiotherapy in FaDu cells

Abstract

Radioresistance causes a major problem for improvement of outcomes of patients treated with radiation. Targeting for DNA repair deficient mechanisms is a hallmark of sensitization to resistance. We tested whether Olaparib, a (poly) ADP‐ribose polymerase (PARP) inhibitor, can sensitize the radioresistant FaDu cells to radiotherapy. Radioresistant FaDu cells, called FaDu‐RR cells, were used as the radioresistant hypopharyngeal cancer models. The expression of PARP1 was detected in both FaDu and FaDu‐RR cells. The role of Olaparib in radiosensitization was analysed with several assays including clonogenic cell survival, cell proliferation and cell cycle, and radioresistant xenograft. High expression of PARP1 had a significant effect on enhancing radioresistance in FaDu‐RR cells compared with FaDu cells. After treatment of Olaparib, FaDu‐RR cells showed significantly less and smaller surviving colonies, lower proliferation ability and G2/M arrest than those in the group without treatment. Moreover, Olaparib significantly reduced growth of tumours in FaDu‐RR cell xenografts treated with ionizing radiation. Olaparib can significantly inhibit PARP1 expression and consequently has significant effects on radiosensitization in FaDu‐RR cells. These results indicate that Olaparib may help individualize treatment and improve their outcomes of hypopharyngeal cancer patients treated with radiation.

Radiosensitizing Effect of Bromelain Using Tumor Mice Model via Ki-67 and PARP-1 Inhibition

“…Other reports indicated that PARP-1 inhibition effectively sensitizes cancer cells to IRR in both in vitro and in vivo models. 8 , 62 , 63 Additionally, in previous studies BL showed an inhibition in PARP-1 cellular proteins, indicating that BL induces cell death mainly through apoptosis and regression in DNA repair mechanisms. 64 , 65 Since the essential role of PARP is double and single strand break (DSB and SSB) recognition and repair, the underlying mechanism of radiosensitization by PARP inhibitors has been suggested to be caused by a delay in DSB and SSB repair processing, resulting in DNA break accumulation and cell death, 66 , 67 especially for tumors with DNA repair defects, such as BRCA mutations.…”

“…42 Inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of ionizing radiation and PARP inhibition has the potential to improve radiotherapy. 8,68 ROS synthesized during mitochondrial respiration exacerbate the DNA damage caused by radiotherapy. 69 ROS levels may influence the extent to which cancer cells are resistant to therapies like radiotherapy.…”

“… 42 Inhibition of PARP activity can sensitize hypoxic cancer cells and the combination of ionizing radiation and PARP inhibition has the potential to improve radiotherapy. 8 , 68 …”

“…7 Targeting for DNA repair-deficient mechanisms, inhibiting tumor cell proliferation, and increasing lipid peroxidation and ROS contents are considered major hallmarks of sensitization to resistance. 8 - 10 …”

CDCA2 promotes tumorigenesis and induces radioresistance in oesophageal squamous cell carcinoma cells

“…The persistence of γH2AX lesions has previously been demonstrated to be associated with radiosensitivity and the loss of lesions depends on effective DNA repair. As DNA is the main target of ionizing radiation and that DNA DSBs are a key lesion that causes cell death, CDCA2 knockdown can increase ESCC sensitivity to X-ray radiation (31,33).…”