Radio-selective effects of a natural occurring muscle-derived dipeptide in A549 and normal cell lines

Norma Ybarra,Jan Seuntjens

doi:10.1038/s41598-019-47944-5

Abstract

Radiotherapy (RT) causes morbidity and long-term side effects. A challenge in RT is to maximize cancer cells killing while minimizing damage to normal tissue. The ideal radio-protector selectively improves survival and limits damage to normal tissues while reducing survival of cancer cells. Muscle-derived dipeptide, L-carnosine (CAR) is a potent antioxidant, with radio-protective, but also anticancer properties, affecting the cell cycle of cancer cells. We tested CAR effects in lung cancer cells, differentiated and undifferentiated normal cells. We hypothesized that CAR antioxidant properties will confer protection to the two normal cell lines against RT, while preventing lung cancer cell proliferation, and that CAR may act as a radiosensitizer of lung cancer cells due to its effects on cell-cycle progression of cancer cells. Under the experimental conditions reported here, we found that CAR increased radio-sensitivity of lung (A549) cancer cells by increasing the percentage of cells in G2/M (radiosensitive) phase of cell cycle, it negatively affected their bioenergetics, therefore reduced their viability, and DNA-double strand break repair capacity. CAR had either no effect or reduced RT-induced damage in normal cells, depending on the cell type. CAR is a versatile natural occurring compound, that could improve RT-induced lung cancer cells killing, while reducing the damage to normal differentiated and undifferentiated cells.

Highlights

Cancer is one of the leading causes of mortality and morbidity worldwide (World Health Organization, https:// www.who.int/cancer/en/)
In the case of bone marrow adherent cells (BMACs), CAR did not affect the total number of colonies in the absence of radiation (Dose 0 Gy), and when BMACs were irradiated with increasing doses, CAR did not significantly affect the total number of colonies (Fig. 1B)
The survival fraction of A549 cells pretreated with CAR was significantly lower (p < 0.05) than the survival fraction of A549 cells treated with radiation (RT) alone at doses higher than 2.5 Gy (Fig. 1C), this effect was not observed in BMACs, for which there was no significant difference between cells pretreated with CAR, and the BMACs with RT alone, for all the doses (Fig. 1D)

Summary

Introduction

Cancer is one of the leading causes of mortality and morbidity worldwide (World Health Organization, https:// www.who.int/cancer/en/). In addition to surgery and chemotherapy, radiation therapy is an important treatment modality used in cancer treatment. The sustained effects of these treatments lead to normal tissue toxicities causing acute and late morbidities (for review see[2,4]). Often the combination of these treatments exacerbates the deleterious effects in normal tissue and surviving cancer cells could become resistant to these treatments[5]. Chemotherapeutic agents are highly toxic and do not discriminate between normal and cancer cells, these agents often cause severe side effects and could lead to secondary malignancies (for review see[6]). Even though RT is a more localized therapy, it causes important normal tissue toxicities[2]. The perfect scenario will be to improve current treatment approaches without damaging normal tissues

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