Abstract
Background and PurposeTo understand the mechanisms involved in the strong killing effect of carbon-ion beam irradiation on cancer cells with TP53 tumor suppressor gene deficiencies.Materials and MethodsDNA damage responses after carbon-ion beam or X-ray irradiation in isogenic HCT116 colorectal cancer cell lines with and without TP53 (p53+/+ and p53-/-, respectively) were analyzed as follows: cell survival by clonogenic assay, cell death modes by morphologic observation of DAPI-stained nuclei, DNA double-strand breaks (DSBs) by immunostaining of phosphorylated H2AX (γH2AX), and cell cycle by flow cytometry and immunostaining of Ser10-phosphorylated histone H3.ResultsThe p53-/- cells were more resistant than the p53+/+ cells to X-ray irradiation, while the sensitivities of the p53+/+ and p53-/- cells to carbon-ion beam irradiation were comparable. X-ray and carbon-ion beam irradiations predominantly induced apoptosis of the p53+/+ cells but not the p53-/- cells. In the p53-/- cells, carbon-ion beam irradiation, but not X-ray irradiation, markedly induced mitotic catastrophe that was associated with premature mitotic entry with harboring long-retained DSBs at 24 h post-irradiation.ConclusionsEfficient induction of mitotic catastrophe in apoptosis-resistant p53-deficient cells implies a strong cancer cell-killing effect of carbon-ion beam irradiation that is independent of the p53 status, suggesting its biological advantage over X-ray treatment.
Highlights
Carbon-ion radiotherapy has been provoking interest in the field of cancer therapy
To explore the mechanisms underlying the p53 status-independent cell-killing activity of carbon-ion beam irradiation, the modes of cell death induced by X-ray or carbon-ion beam irradiation were assessed (Figs. 2, 3). p53+/+ and p53-/- cells were irradiated with doses of X-ray or carbon-ion beams that were similar to the D10 for p53+/+ cells (X-ray, 4 Gy; carbon-ion beams, 1.5 Gy)
The induction of senescence was not evident in all experimental conditions (Fig. 2). This result was confirmed by senescence-associated b-galactosidase staining assays, in which the fraction of staining-positive cells was less than 2% for both cell lines exposed to X-ray or carbon-ion beam irradiation. These data indicated that apoptosis and mitotic catastrophe is the major mode of cell death in p53+/+ cells and p53-/- cells, respectively, both after exposure to X-ray and carbon-ion beam irradiation, and that carbon-ion beam irradiation induces mitotic catastrophe more effectively than X-ray irradiation in apoptosis-resistant p53-/- cells
Summary
Carbon-ion radiotherapy has been provoking interest in the field of cancer therapy. Carbon-ion beams have advantageous properties over X-ray; a superior dose distribution associated with the sharp penumbra and the Bragg peak, and strong cell-killing effect [1, 2]. A recent study in which carbon-ion radiotherapy was used to treat patients with rectal cancer reported a 5-year local control and overall survival rates of 97% and 51% for post-operative recurrent cases [3]. This rate is superior to the 5-year overall survival rates (0240%) that are typically achieved by conventional X-ray radiotherapy or surgical resection [3, 4]. Conclusions: Efficient induction of mitotic catastrophe in apoptosis-resistant p53deficient cells implies a strong cancer cell-killing effect of carbon-ion beam irradiation that is independent of the p53 status, suggesting its biological advantage over X-ray treatment
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