High LET Heavy Ion Radiation Induces p53-Independent Apoptosis

Abstract

Conventional clinical treatments with X-rays provide an effective modality for widely various human cancers, however, therapeutic results are sometimes poor. Many mutations have been reported to be in the p53 gene in advanced human cancers. The p53 plays a pivotal role in the pathway which controls apoptosis, cell growth and cell proliferation, and mutations or deletions in the p53 gene lead to resistance to cancer therapy. The involvement of the p53 gene in determining the sensitivity of many cell types toward low linear energy transfer (LET) radiation is now well established. In contrast to low LET radiation, high LET radiation has several potential advantages over X-rays, one of which is the fact that its effects may be independent of cellular p53 gene status. It is conceivable that effective future therapeutic strategies may be designed on the basis of genetic and biochemical events involved in cell death. Therefore, the accurate characterization and quantification of the mode of cell death, such as apoptosis and necrosis, has become increasingly important for the further understanding of the biological effectiveness of high LET radiation. This review discusses the mechanisms of p53-independent apoptosis by high LET radiation.

Low and high linear energy transfer radiation sensitization of HCC cells by metformin

“…They have suggested that low-LET and high-LET radiation trigger different apoptotic pathways. While low-LET radiation mediated p53-induced caspase-8-dependent apoptosis, damage from high-LET radiation could induce mitochondria-dependent and p53-independent apoptosis through caspase-9 [29]. This result correlates with our data showing higher caspase-9 than caspase-8 activity in cells treated with combined metformin and neutron radiation.…”

Cellular and molecular portrait of eleven human glioblastoma cell lines under photon and carbon ion irradiation

“…By contrast, cell death induced by irradiation with carbon ions is independent of p53 [20]. Here we firstly observed that the radiosensitivity of GBM cells does not depend on p53 or MGMT status, whatever the type of irradiation, and secondly that the efficiency of carbon beam irradiation is about twofold higher than that of photons.…”

Radiation countermeasure agents: an update

“…Another issue arises from the fact that most efficacy studies reported so far have utilized low linear energy transfer (LET) IR such as g rays and X-rays for irradiation. Future work will need to document the efficacy of selected agents against the damage produced by high LET particle radiations, since they are utilized in hadrontherapy, are major components of IR exposure from the detonation of nuclear devices and differ in some of their biological effects from low LET radiations [163]. Moreover, different agents appear to ameliorate only certain aspects of IR injury such that combining several compounds with distinct and complementary spectrum of activity may be required for optimal medical prevention or therapy of ARS.…”