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

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.

Synthesis and biological evaluation of a series of 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-2-substituted tetrahydroisoquinoline derivatives.

Multidrug resistance in cancer is a major cause of failure in cancer chemotherapy. In search of new compounds with strong reversal activity and simple molecular structure, we have synthesized a series of compounds in which different substituents were linked to the 2-position of the 6,7-dimethoxy-1-(3,4-dimethoxybenzyl)- tetrahydroisoquinoline system. Compounds were analyzed for their cytotoxicity by MTT in K562 cell line in vitro, all of the derivatives exhibited little cytotoxic activity. In the meantime, these compounds were evaluated by MTT in K562/A02 cell line in vitro, 6e, 6h and 7c exhibited similar or more potent activities than verapamil with the IC50 values at 0.66, 0.65 and 0.96µM, and with the ratio factor of 24.13, 24.50 and 16.59, respectively.

dbHCCvar: a comprehensive database of human genetic variations in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer with a high mortality rate. The complete pathogenesis of HCC is not completely understood, and highly efficient therapy is still unavailable. In the past several decades, various genetic variations such as mutations and polymorphisms have been reported to be associated with HCC risk, progression, survival, and recurrence. However, to our knowledge, these genetic variations have not been comprehensively and systematically compiled. In this study we constructed dbHCCvar, a free online database of human genetic variations in HCC. Eligible publications were collected from PubMed, and detailed information and major research data from each eligible study were then extracted and recorded in our database. As a result, dbHCCvar contains almost all human genetic variations reported to be associated or not associated with HCC risk, clinical pathology, drug reaction, survival, or recurrence to date. It is expected that dbHCCvar will function as a useful tool for researchers to facilitate the search and identification of new genetic markers for HCC. dbHCCvar is free for all visitors at http://GenetMed.fudan.edu.cn/dbHCCvar.