Radiotherapy is one of the modalities in the treatment of
glioblastoma patients, but
glioma tumors are resistant to radiation and also
chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve
radiotherapy. PARP
enzymes and
topoisomerase I enzymes have a critical role in repairing DNA damage in
tumor cells. Thus, inhibiting activity of these
enzymes helps stop DNA damage repair and increase
DSB lethal damages. In the current study, we investigated the combination of
TPT as a
topoisomerase I inhibitor, and
A-966492 as a novel
PARP inhibitor for further radiosensitization. U87MG cells (a human
glioblastoma cell line) were cultured in
Poly-Hema coated flasks to reach 300 μm-diameter spheroids. Treatments were accomplished by using non-toxic concentrations of
A-966492 and
Topotecan. The surviving fraction of treated cells was determined by clonogenic assay
after treatment with drugs and 6 MV X-ray. The γ-H2AX expression was measured by an immunofluorescence staining method to examine the influence of
A-966492,
TPT and radiation on the induction of double stranded DNA breaks. Treatments using the
A-966492 drug were conducted in concentration of 1 μM. Combining
A-966492 and
TPT with radiation yielded enhanced cell killing, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) 1.39 and 1.16 respectively. Radio- and chemo-sensitization was further enhanced when
A-966492 was combined with both X-ray and
TPT, with SER50 of 1.53. Also γ-H2AX expression was higher in the group treated with a combination of drugs and radiation.
A-966492 is an effective
PARP inhibitor and has significant radio-sensitivity on U87MG spheroids. By accumulating cells in the S phase and by inhibiting the DNA damage repair,
TPT enhanced radio-sensitivity.
A-966492 combined with
TPT as a
topoisomerase I inhibitor had additive radio-sensitizing effects. As a result, applying PARP and
topoisomerase I inhibitors can be a suitable strategy for improving
radiotherapy in clinics.