Pifithrin-α as a Potential Cytoprotective Agent in Radiotherapy: Protection of Normal Tissue without Decreasing Therapeutic Efficacy in Glioma Cells

Abstract

Activation of p53 has been causally linked to normal tissue damage after irradiation. Pifithrin-α (PFT-α), a specific inhibitor of p53, has been suggested as a combinatory agent in the treatment of p53-deficient tumors in which inhibition of p53 would not compromise therapeutic efficacy but would decrease p53-mediated side effects in normal tissue. We tested this concept for radiotherapy of p53-deficient and -proficient glioma. We observed significant interaction of PFT-α with radiation-induced G(1) checkpoint activation and plating efficiency only in glioma cells expressing at least one wild-type allele of p53. This interaction was correlated with PFT-α-mediated inhibition of radiation-induced expression of the p53 target gene p21(Waf1). Despite inhibition of p53 function we did not observe significant changes in radiosensitivity after treatment with PFT-α in either p53-deficient or p53-proficient tumor cells. We confirmed these results in p53-proficient lung cancer cells. In contrast, PFT-α significantly increased the fraction of normal astrocytes and fibroblasts surviving irradiation; this was accompanied by improved DNA damage repair, speaking against an accumulation of cells with genetic lesions after PFT-α treatment. In conclusion, PFT-α might prove useful in protecting normal tissue from the side effects of radiotherapy without reducing the efficacy of treatment for both p53-proficient and -deficient tumors.

Expanding the therapeutic index of radiation therapy by normal tissue protection

“…To prevent and inhibit radiation-induced toxicity, the early prevention of epithelial, endothelial, and stem cell deaths is one of the primary options that can be proposed. These interventions imply the administration of drugs delivered prophylactically (Table 1) including inhibitors of pro-apoptotic molecules, such as the transient blockade of p53 (Pifithrin); 10,11 the inhibition of p-53 upregulated modulator of apoptosis (Puma Inhibitors) or the inhibition of the ceramide pathway in endothelial cells. 16,17 Alternatively, stimulation of antiapoptotic molecules such as NF-ҡB by the flagellin-derivative, CBLB502 18,19 protects microvascular endothelial cells from radiation-induced death.…”

Contemporary Radiation Countermeasure

“…Activation of p53 has been linked to normal tissue damage after irradiation, as p53 eliminates the damaged cell by apoptosis 42 . Inhibitors of p53 like pifithrin-alpha, particularly in cells that were inadvertently exposed to radiation have the potential to salvage the tissue 43 (Fig. 3).…”

“…In glioma cells, it was shown that there was an increase in survival of normal astrocytes and fibroblasts post-irradiation. It is also important to note that there were no changes in radiosensitivity of the tumor to irradiation using pifithrinalpha 43 . Therefore, this agent may prove valuable in protecting normal tissues from the side effects of radiotherapy while maintaining treatment efficacy.…”