Int J Cancer Manag. 2020 December; 13(12):e106845. Published online 2020 December 9. doi: 10.5812/ijcm.106845. Research Article Study of Synergistic and Protective Effects of Three Different Polar Saffron Extracts and Photon Radiation on Human Colorectal Cancer Cells (HT-29) and Normal Human Fibroblasts Mahnaz Nourbakhsh 1 , Amin Hosseinzade 1 , Jamshidkhan Chamani 2 , Ameneh Sazgarnia 3 and Roham Salek 1, * 1 Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 2 Department of Biochemistry and Biophysics, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran 3 Medical Physics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran * Corresponding author: Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. Email: salekr@mums.ac.ir Received 2020 June 25; Revised 2020 September 11; Accepted 2020 September 13. Abstract Background: There are some hypotheses about radiation-sensitizing and radiation-protective effects of antioxidants. Saffron, dried stigmas of Crocus sativus L., is a precious medicinal plant that contains an impressive variety of plant compounds such as crocin, crocetin, and safranal that act as antioxidants. The present study examined the cytotoxic effects of saffron extracts with different polarity and their synergism or protective effects with radiation on a colorectal cancer cell line (HT-29) and normal human fibrob- lasts. Objectives: The aim was to find a natural agent to improve radiotherapy efficacy. Methods: HT-29 colorectal cancer cells and normal human fibroblasts were cultured in RPMI1640 medium, incubated with different concentrations of different saffron extracts (50-250 μg/ml), and then were exposed to a dose of 8 Gy of X-rays. The cytotoxicity effect was determined by the MTT assay. Results: Saffron extracts decreased cell viability in HT-29 colorectal cancer cells and normal human fibroblasts as a concentration- dependent manner. Combination radiotherapy with polar saffron extract in most doses showed synergistic effects on HT-29 cell death while it did not show any distinctive synergistic effect in normal cells. Semi-polar and non-Polar extracts just in low doses had synergistic effects on tumor cells. These two extracts did not show any protective effects on normal cells. Conclusions: Among the various saffron extracts, polar saffron extract and low doses of non-polar saffron extract in combination with radiation increase radiation sensitivity and cell death in tumor cells, while they do not increase radiation sensitivity in normal cells and even protect normal cells to some extent. Keywords: Crocus, HT29 Cells, Fibroblasts 1. Background Radiotherapy is a well-known modality of cancer treat- ment artillery. In order to obtain optimal results in radio- therapy, an appropriate balance must be established be- tween the fraction size, the total radiation dose, and the natural tissue threshold. In fact, the effects of radiation on the natural cells and adjacent tissues of the tumor limit the use of higher doses in radiotherapy. Ionizing radia- tion, as low Linear Energy Transfer (LET) as x-rays or γ - rays, creates free radicals in the cell. These radicals are highly reactive and react with cellular macromolecules such as Deoxyribonucleic acid (DNA), Ribonucleic acid (RNA), and proteins, and will lead to disruptions and cell death. Radia- tion moderator agents that can specifically protect normal cells, but not cancer cells against radiation, or specifically increase the sensitivity of cancer cells to radiation, would improve the efficacy of radiotherapy (1). In recent decades, in order to find suitable radio- protector and radio-synthesizer agents, wide studies have been done and various factors have been introduced. Among them, antioxidants that protect the cells against free radicals and oxidative stress are highly regarded. There is a hypothesis that suggests that high doses of di- etary antioxidants (vitamins C and E, and β-carotene) may increase tumor response to radiotherapy and decrease the toxicity on normal cells (2). Among the herbs containing antioxidants, saffron can Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.