Identification of icaritin derivative IC2 as an SCD-1 inhibitor with anti-breast cancer properties through induction of cell apoptosis

Abstract

Background Breast cancer is the most common malignancy affecting women, yet effective targets and related candidate compounds for breast cancer treatment are still lacking. The lipogenic enzyme, stearoyl-CoA desaturase-1 (SCD1), has been considered a potential target for breast cancer treatment. Icaritin (ICT), a prenylflavonoid derivative from the Traditional Chinese Medicine Epimedii Herba, has been reported to exert anticancer effects in various types of cancer. The purpose of the present study was to explore the effect of the new ICT derivative, IC2, targeting SCD1 on breast cancer cells and to explore the specific mechanism. Methods Immunohistochemistry and semiquantitative evaluation were performed to detect the expression level of SCD1 in normal and tumor samples. Computer-aided drug design (CADD) technology was used to target SCD1 by molecular docking simulation, and several new ICT derivatives were prepared by conventional chemical synthesis. Cell viability was evaluated by an MTT assay and dead cell staining. SCD1 expression in cancer cells was determined by Western blot and qRT-PCR analyses. The enzymatic activity of SCD1 was evaluated by detecting the conversion rate of [d31] palmitic acid (PA) using Gas chromatography-mass spectrometry (GC–MS). DAPI staining, flow cytometry and Western blot were used to detect cell apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) assays were used to determine cell mitochondrial function. Lentiviral transduction was utilized to generate SCD1-overexpressing cell lines. Results We found that SCD1 was overexpressed and correlated with poor prognosis in breast cancer patients. Among a series of ICT derivatives, in vitro data showed that IC2 potentially inhibited the viability of breast cancer cells, and the mechanistic study revealed that IC2 treatment resulted in ROS activation and cellular apoptosis. We demonstrated that IC2 inhibited SCD1 activity and expression in breast cancer cells in a dose-dependent manner. Moreover, SCD1 overexpression alleviated IC2-induced cytotoxicity and apoptosis in breast cancer cells. Conclusions The new ICT derivative, IC2, was developed to induce breast cancer cell apoptosis by inhibiting SCD1, which provides a basis for the development of IC2 as a potential clinical compound for breast cancer treatment.

Icaritin Derivative IC2 Induces Cytoprotective Autophagy of Breast Cancer Cells via SCD1 Inhibition

“…The ICT derivative IC2 ( Figure 1 ) inhibited SCD1 activity in a dose-dependent manner and induced apoptosis by the mitochondrial pathway in MCF-7 cells, which has been demonstrated in previous studies [ 10 ]. To understand whether autophagy played an important role in IC2-induced cell death, we examined the related indicators of autophagy.…”

“…Compared to ICT and other ICT derivates, IC2 showed the highest binding free energies (−114.9 kcal/mol) with SCD1, and the most significant inhibition of breast cancer cell proliferation. The subsequent experiments also confirmed that IC2 truly inhibited SCD1 activity in a dose-dependent manner and induced apoptosis in breast cancer cells [ 10 ]. Therefore, in this study, we further explored the mechanism of IC2-induced anti-breast cancer effect in vitro and in vivo, and we demonstrated that IC2 mediated cytoprotective autophagy in breast cancer cells through SCD1 inhibition, which provided a promising strategy for clinicians to explore the treatment of breast cancer.…”

“…Our previous study had revealed that IC2-induced antiproliferation effect and apoptosis were dependent on the inhibition of SCD1 expression and activity [ 10 ]. To further explore the relationship between SCD1 and IC2-induced autophagy in MCF-7 cells, we successfully constructed an SCD1-overexpressing MCF-7 cell line (LV-SCD1).…”

“…Therefore, ICT should be chemically modified to expand the antitumor effect. Our previous study had identified that IC2 can markedly induce the apoptosis of breast cancer cells by SCD1 inhibition in vitro [ 10 ]. Herein, we proved that IC2 could exert an antitumor effect in the 4T1 breast cancer xenograft model, which further proves the clinical potential of IC2 as a candidate compound on SCD1-targeted therapy.…”

“…Furthermore, over-expressed SCD1 in cancer cells enriches membrane phospholipids with MUFA, producing a more fluid lipid membrane, and induces cancer cell proliferation, migration and invasion [ 4 ]. Our previous study also revealed that SCD1 was overexpressed and correlated with poor prognosis in breast cancer patients, and could be a novel therapeutic target for breast cancer [ 10 ].…”