Ellagic Acid Enhances Apoptotic Sensitivity of Breast Cancer Cells to γ-Radiation

Abstract

Herbal polyphenols have gained increased significance because of the promises they hold in the prevention and treatment of cancer. There exists an enormous opportunity for the screening and valuation of natural dietary compounds in the development of an effective chemopreventive drug and radiosensitizer that may be of practical use for patients undergoing cancer therapy. This study describes the effect of the flavonoid ellagic acid (EA) on gamma-irradiated human breast cancer MCF-7 cells in vitro when administered alone or in combination with radiation. It was interesting to find the radioprotective effect of EA on NIH3T3, which is a normal cell line. Irradiation of breast tumor cells in the presence of EA (10 μM) to doses of 2 and 4-Gy gamma radiation produced a marked synergistic tumor cytotoxicity while it was found to aid recovery from the radiation damage to NIH3T3 cells. When cells were given a combined treatment of EA and radiation, the cell death increased to 21.7% and 20.7% in the 2 and 4-Gy-treated cells respectively, significantly (P < 0.05) reducing the capacity of MCF-7 cells to form colonies. Even at 24 h, 38 foci/cell were observed in samples that were given the combined treatment, suggesting the cells' inability in repairing the damage. Also, increased apoptosis in EA+ 2Gy (50%) and EA+ 4 Gy (62%)-treated cells was observed in the the sub-G1 phase of the cell cycle. A 6.2-fold decrease in the mitochondrial membrane potential was observed in the combined treatment of EA and IR that facilitated the upregulation of pro-apopttotic Bax and downregulation of Bcl-2, pushing the MCF-7 cells to undergo an apoptotic cell death. It is suggested that EA may be a potential drug adjuvant for improving cancer radiotherapy by increasing tumor toxicity and reducing the normal cell damage caused by irradiation.

A Pharmacological Update of Ellagic Acid

“…Ellagic acid also has potential as a drug adjuvant for enhancing cancer radiotherapy due to its ability not only to improve apoptotic sensitivity on γ-irradiated human breast cancer MCF-7 cells, but also to upregulate Bax and downregulate Bcl-2, leading cells to undergo apoptotic death. While it was found to have a radio-protective effect on normal cell lines, combined treatment with ellagic acid (10 μM) and doses of 2-and 4-Gy γ radiation on MCF-7 exhibited synergistic tumor cytotoxicity [191].…”

“…Breast MCF-7 Cell cycle arrest G 0 /G 1 via TGF-β/Smads pathway Upregulate Bax and downregulate Bcl-2 ↑ synergistic cytotoxicity and apoptotic sensitivity on γ-irradiated cells ↓ Akt/mTOR activation [189][190][191] Cervical HeLa Upregulate IGFBP7and block Akt/mTOR pathway [194] Colon…”

Enhanced anticancer activity and oral bioavailability of ellagic acid through encapsulation in biodegradable polymeric nanoparticles

“…[10][11][12] Therapeutically, EA has been proclaimed to be effective in the regression of various kinds of tumors, involving but not limited to lung cancer, colorectal carcinoma, esophageal cancer, metastatic melanoma, hepatocellular carcinoma, tongue cancer, breast cancer, bladder cancer, endometrial carcinoma, and prostate cancer. 4,16,[18][19][20][21][22][23][24][25] Whereas the pharmacological effect of EA has been broadly considered and permitted for the management of a vast spectrum of cancer, it still has poor aqueous solubility and poor bioavailability that offer minimal therapeutic benefit and restrict its full clinical use. 26 Oral administration showed a poor absorption, metabolism in gastrointestinal tract, first-pass effect, and rapid elimination, 19,27,28 which are reported as the main causes of its low bioavailability.…”

Antiinflammatory and anti‐cancer activities of pomegranate and its constituent, ellagic acid: Evidence from cellular, animal, and clinical studies

“…EA augmented the cell death, upregulated the pro-apoptotic Bax, downregulated the antiapoptotic Bcl-2 and diminished the capacity of MCF-7 cells to form colonies following radiation. Therefore, EA may be potential candidate for improving the cancer radiotherapy (Ahire, Kumar, Mishra, & Kulkarni, 2017).…”