The Inhibitory Effect of Curcumin on Hypoxia Inducer Factors (Hifs) as a Regulatory Factor in the Growth of Tumor Cells in Breast Cancer Stem-Like Cells
Mehrnaz Asadi Sarighieh, Vahideh Montazeri, Amir Shadboorestan, Mohammad Hossein Ghahremani, Seyed Nasser Ostad
Abstract
Abstract Hypoxia in the microenvironment is related to chemotherapy resistance, tumor progression, and metastasis. Curcumin, as a phenolic compound extracted from the turmeric, has been used as an anti-cancer agent with low toxicity in recent years. Since curcumin has inhibitory activities against hypoxia-inducible factors (HIFs) in several cancers, this study was conducted to examine the effect of curcumin on MCF-7 cells and cancer stem-like cells (CS-LCs) under hypoxic and normoxic conditions. CS-LCs were isolated from MCF-7 cells using the magnet activated cell sorting (MACS) method based on CD44 +/ CD24 - surface markers. The effects of curcumin on the viability of MCF-7 cells and CS-LCs were examined in hypoxic and normoxic conditions using the MTT test. The effects of curcumin on apoptosis and cell cycle of CS-LCs and MCF-7 cells were analyzed using flow cytometry. Moreover, the inhibitory effects of curcumin on the levels of HIF-1 and HIF-2α protein in CS-LCs were investigated using the western blot method. Early apoptosis occurred in CSC-LCs more than MCF-7 cells under hypoxic conditions. Flow cytometry assay showed that curcumin caused cell cycle arrest of CSC-LCs and MCF-7 at the G2/M phase under hypoxic conditions while under normoxic conditions, arrest occurred at the G0/G1 phase in MCF-7 cells and at S and G2/M phases in CS-LCs. Based on the results, the curcumin inhibited the expression of HIF-1 by degrading ARNT in CS-LCs. In conclusion, curcumin has inhibitory effects on MCF- 7 cells and CS- LCs and thus may be used as an antitumor agent.