Inhibition of cancer stem cell like cells by a synthetic retinoid

Junwei Chen, Xin Cao, Quanlin An, Yao Zhang, Ke Li, Wenting Yao, Fuchun Shi, Yanfang Pan, Qiong Jia, Wenwen Zhou, Fang Yang, Fuxiang Wei, Ning Wang () and Biao Yu ()
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Junwei Chen: Huazhong University of Science and Technology
Xin Cao: Chinese Academy of Sciences
Quanlin An: Chinese Academy of Sciences
Yao Zhang: Huazhong University of Science and Technology
Ke Li: Huazhong University of Science and Technology
Wenting Yao: Huazhong University of Science and Technology
Fuchun Shi: Chinese Academy of Sciences
Yanfang Pan: Chinese Academy of Sciences
Qiong Jia: Huazhong University of Science and Technology
Wenwen Zhou: Huazhong University of Science and Technology
Fang Yang: Huazhong University of Science and Technology
Fuxiang Wei: Huazhong University of Science and Technology
Ning Wang: Huazhong University of Science and Technology
Biao Yu: Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Developing novel drugs that can abrogate the growth and metastasis of malignant tumors is a major challenge for cancer researchers. Here we describe a novel synthetic retinoid, namely WYC-209, which inhibits proliferation of malignant murine melanoma tumor-repopulating cells (TRCs), known to resist conventional drug treatment, with an IC50 of 0.19 μM in a dose-dependent manner. WYC-209 also inhibits proliferation of TRCs of human melanoma, lung cancer, ovarian cancer, and breast cancer in culture. Interestingly, the treated TRCs fail to resume growth even after the drug washout. Importantly, the molecule abrogates 87.5% of lung metastases of melanoma TRCs in immune-competent wild-type C57BL/6 mice at 0.22 mg kg−1 without showing apparent toxicity. Pretreating the melanoma TRCs with retinoic acid receptor (RAR) antagonists or with RAR siRNAs blocks or reduces the inhibitory effect of the molecule, suggesting that the target of the molecule is RAR. WYC-209 induces TRC apoptosis and pretreating the TRCs with caspase 3 inhibitor or depleting caspase 3 with siRNAs substantially rescues growth of TRCs from WYC-209 inhibition, suggesting that WYC-209 induces TRCs apoptosis primarily via the caspase 3 pathway. Our findings demonstrate the promise of the new retinoid WYC-209 in treating malignant melanoma tumors with high efficacy and little toxicity.

Date: 2018
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DOI: 10.1038/s41467-018-03877-7

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