Cellular and molecular effects of protons: Apoptosis induction and potential implications for cancer therapy

Due to their ballistic precision, apoptosis induction byprotons could be a strategy to specifically eliminateneoplastic cells. To characterize the cellular and moleculareffects of these hadrons, we performed dose-response andtime-course experiments by exposing different cell lines(PC3, Ca301D, MCF7) to increasing doses of protons andexamining them with FACS, RT-PCR, and electron spin resonance(ESR). Irradiation with a dose of 10 Gy of a 26,7 Mevproton beam altered cell structures such as membranes,caused DNA double strand breaks, and significantlyincreased intracellular levels of hydroxyl ions, are activeoxygen species (ROS). This modified the transcriptome ofirradiated cells, activated the mitochondrial (intrinsic) pathwayof apoptosis, and resulted in cycle arrest at the G2/Mboundary. The number of necrotic cells within the irradiatedcell population did not significantly increase with respectto the controls. The effects of irradiation with 20 Gy werequalitatively as well as quantitatively similar, but exposureto 40 Gy caused massive necrosis. Similar experiments withphotons demonstrated that they induce apoptosis in a significantlylower number of cells and in a temporally delayedmanner. These data advance our knowledge on the cellularand molecular effects of proton irradiation and could beuseful for improving current hadrontherapy protocols.