The prenylated flavonoid icaritin (ICT) is currently undergoing phase 3 clinical trial for the treatment of advanced hepatocellular carcinoma (HCC), based on a solid array of preclinical and clinical data. The antitumor activity originates from the capacity of the drug to modulate several signaling effectors in cancer cells, mainly the estrogen receptor splice variant ERα36, the transcription factors STAT3 and NFκB, and the chemokine receptor CXCR4. Recent studies have implicated additional components, including different microRNAs, the generation of reactive oxygen species and the targeting of sphingosine kinase-1. ICT also engages the RAGE-HMGB1 signaling route and modulates the apoptosis/autophagy crosstalk to promote its anticancer activity. In addition, ICT exerts profound changes on the tumor microenvironment to favor an immune-response. Collectively, these multiple biochemical and cellular characteristics confer to ICT a robust activity profile which can be exploited to treat HCC, as well as other cancers, including glioblastoma and onco-hematological diseases such as chronic myeloid leukemia. This review provides an update of the pharmacological properties of ICT and its metabolic characteristics. It also addresses the design of derivatives, including both natural products and synthetic molecules, such as SNG1153 also in clinical trial. The prenylated flavonoid ICT deserves attention as a multifunctional natural product potentially useful to improve the treatment of advanced hepatocellular carcinoma.

2017-07-04·Oncotarget

Targeting BCR-ABL+ stem/progenitor cells and BCR-ABL-T315I mutant cells by effective inhibition of the BCR-ABL-Tyr177-GRB2 complex

Article

作者: Meng, Kun ; Ding, Hongxia ; Chen, Min ; Lin, Qingcong ; Turhan, Ali G. ; Jiang, Xiaoyan

Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm. Interestingly, new pre-clinically-validated analogs of Icaritin (SNG162 and SNG1153), which target abnormal ERα36 activity, inhibit cell growth and induce apoptosis of BCR-ABL+ leukemic cells, particularly BCR-ABL-T315I mutant cells. A combination of SNG inhibitors and TKI selectively eliminates treatment-naïve TKI-insensitive stem/progenitor cells while sparing healthy counterparts. Oral TKI dasatinib combined with potent SNG1153 inhibitor effectively eliminates infiltrated BCR-ABL+ blast cells and enhances survival of mice. Importantly, a unique mechanism of SNG inhibition was uncovered by demonstrating a marked interruption of the BCR-ABLTyr177-GRB2 interaction, leading to inhibition of the downstream RAS/MAPK pathway. This new combination therapy may lead to more effective disease eradication, especially in patients at high risk of TKI resistance and disease progression.

2016-07-19·Oncotarget

A novel anticancer agent SNG1153 inhibits growth of lung cancer stem/progenitor cells

Article

作者: Fu, Xueqi ; Wang, Jing ; Zhu, Hai ; Zhou, Congya ; Liu, Shiyang ; Guo, Yuming ; Ma, Junfeng ; Meng, Kun ; Lin, Qingcong ; Wang, Jun ; Han, Yuqing ; Wang, Zhaoyi ; Jin, Mingji

Lung cancer is the leading cause of cancer-related death in both men and women. Lung cancer contains a small population of cancer cells with stem-like features known as cancer stem cells (CSCs). CSCs are often more resistant to current therapeutic treatments. Thus, it is urgent to develop a novel agent that is able to inhibit CSCs growth. In this study, we examined the ability of SNG1153, a novel chemical agent to inhibit the growth of lung CSCs. We found that SNG1153 inhibited growth and induced apoptosis in established lung cancer cells. We also found that SNG1153 inhibited the tumorsphere formation and decreased CD133-positive (lung CSC marker) cancer cells. SNG1153 was able to attenuate tumor formation in NOD/SCID (non-obese diabetic/severe combined immunodeficient) mice injected with lung tumorsphere cells. We further demonstrated that SNG1153 induced β-catenin phosphorylation and down-regulated β-catenin. Our results thus demonstrate that SNG1153 effectively inhibits the growth of lung CSCs and suggest that SNG1153 may be a novel therapeutic agent to treat human lung cancer.

100 项与氟可拉定相关的药物交易

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