A novel superoxide dismutase mimetic sensitizes lung cancer cells to radiation and protects normal cells

Abstract

Lung cancer remains the leading cause of cancer mortality worldwide, and ionizing radiation (IR) is considered one of the most successful strategies to treat such an aggressive disease. However, the large doses of IR required to effectively kill cancer cells induce significant damage to normal cells, leading to treatment failure. In the present study, we investigated the effects of GC4419, a newly developed superoxide dismutase mimetic, alone and in combination with different doses of IR on cell proliferation of normal and non‐small cell lung cancer; the molecular mechanisms of such effects were also studied. Our aim was to investigate the ability of GC4419 to prevent or minimize radiotherapy‐induced adverse effects to normal cells and to enhance the efficacy of low doses of IR to kill cancer cells. Our results revealed that treatment with GC4419 alone inhibited cancer cells proliferation without affecting the viability of normal cells. Notably, combination treatment of GC4419 and IR inhibited cell proliferation of cancer cells more significantly, when compared to IR mono therapy. DNA fragmentation and caspase cleavage were significantly increased following combined GC4419 and IR treatment, indicating activation of apoptosis pathways. Furthermore, GC4419 or IR alone increased the ratio of Bax/Bcl‐2 protein expression, indicating induction of apoptosis. Such an effect was significantly increased following the combined therapy. In conclusion, our study demonstrates that GC4419 can be used as an effective adjuvant to radiation therapy to enhance the efficacy of low dose IR and to protect normal cells against radiation‐induced damage.Support or Funding InformationNIH grants # HL 135648, HL 131941, and EB 016096 to Jay L. ZweierThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.