Abstract
High linear energy transfer (LET) radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator. PNKP (polynucleotide kinase/phosphatase) is an enzyme which plays important role in the non-homologous end joining (NHEJ) DNA repair pathway. It is expected that inhibition of PNKP activity may enhance the efficacy of the charged particle irradiation in the radioresistant prostate cancer cell line PC-3. To test this hypothesis, we investigated cellular radiosensitivity by clonogenic cell survival assay in PC-3 cells.12Carbon ion beam of62 MeVenergy (equivalent 5.16 MeV/nucleon) and with an entrance LET of 287 kev/μm was used for the present study. Apoptotic parameters such as nuclear fragmentation and caspase-3 activity were measured by DAPI staining, nuclear ladder assay and colorimetric caspase-3method. Cell cycle arrest was determined by FACS analysis. Cell death was enhanced when carbon ion irradiation is combined with PNKPi (PNKP inhibitor) to treat cells as compared to that seen for PNKPi untreated cells. A low concentration (10μM) of PNKPi effectively radiosensitized the PC-3 cells in terms of reduction of dose in achieving the same survival fraction. PC-3 cells underwent significant apoptosis and cell cycle arrest too was enhanced at G2/M phase when carbon ion irradiation was combined with PNKPi treatment. Our findings suggest that combined treatment of carbon ion irradiation and PNKP inhibition could enhance cellular radiosensitivity in a radioresistant prostate cancer cell line PC-3. The synergistic effect of PNKPi and carbon ion irradiation could be used as a promising method for carbon-ion therapy in radioresistant cells.
Highlights
Radioresistance is an obstacle in the successful treatment of cancer by low linear energy transfer (LET) radiotherapy using gamma radiation or X-ray radiation [1,2,3,4,5]
The unique physical and biological properties of high LET radiation make it theoretically possible to carry out hypofractionated radiotherapy using a significantly smaller number of fractions than those used in conventional radiotherapy and this has become one of the important reasons to opt for it [8]
To evaluate the synergistic effect of C-ion radiation and PNKP inhibitor (PNKPi) we have choosen four different concentartion of A12B4C3 (0.5μM, 1μM, 5μM and 10μM) with three different doses of C-ion irradiation (0.5Gy, 2Gy and 4Gy) for clonogenic cell survival assay and found that C-ion irradiation causes enhancement in cell death when pretreated with PNKPi“Figs 2C–2F”
Summary
Radioresistance is an obstacle in the successful treatment of cancer by low LET radiotherapy using gamma radiation or X-ray radiation [1,2,3,4,5]. The unique physical and biological properties of high LET radiation make it theoretically possible to carry out hypofractionated radiotherapy using a significantly smaller number of fractions than those used in conventional radiotherapy and this has become one of the important reasons to opt for it [8]. It has many potential advantages over the low LET radiotherapy as it overcomes the radioresistance problem along with permitting dose escalation within the tumor which might result in a better tumor control [9]. It has a smaller oxygen enhancement ratio and reduced cell cycle related radiosensitivity [12,13,14]
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