Heavy-ion irradiation induces a higher frequency of
DNA double strand breaks (DSBs) which must be properly repaired. Critical shortening of telomeres can trigger DNA damage responses such as DSBs. Telomeres are very sensitive to oxidative stress such as ionizing radiation. The
DNA-dependent protein kinase catalytic subunit (
DNA-
PKcs) is the central component in the non-homologous end joining (NHEJ) repair complex and participates in telomere maintenance. Therefore, it is expected to enhance the cell killing effect of heavy-ion irradiation via
DNA-
PKcs inhibition. To test this hypothesis, cellular radiosensitivity was measured by the clonal genetic assay. DNA damage repair was relatively quantified by long PCR. Apoptosis was quantified by flow-cytometric analysis of
annexin V/PI double staining, and senescence was analyzed by
galactosidase activity. Telomere length was semi-quantified by real-time PCR. P53 and p21 expression was determined by western blotting. Our data demonstrated that MCF-7 and HeLa cells with
DNA-
PKcs inhibition were more susceptible to
carbon-ion irradiation than Those without
DNA-
PKcs inhibition. Even though NHEJ was inhibited by the
DNA-
PKcs specific inhibitor,
NU7026, most DNA damage induced by
carbon-ion irradiation was repaired within 24 hours after irradiation in both cell lines. However, potential lethal damage repair (PLDR) could not restore cellular inactivation in
DNA-
PKcs inhibited cells. MCF-7 cells showed extensive senescence and accelerated telomere length reduction, while HeLa cells underwent significant apoptosis after irradiation with
NU7026 incubation. In addition, both cell lines with shorter telomere were more susceptible to
carbon-ion radiation. Our current data suggested that
DNA-
PKcs inhibition could enhance cellular sensitivity to
carbon-ion radiation via disturbing its functional role in telomere end protection. The combination of
DNA-
PKcs inhibition and
carbon-ion irradiation may be an efficient method of
heavy-ion therapy.