2. Academic Validation
  3. Cinchona Alkaloid-Inspired Urea-Containing Autophagy Inhibitor Shows Single-Agent Anticancer Efficacy

Cinchona Alkaloid-Inspired Urea-Containing Autophagy Inhibitor Shows Single-Agent Anticancer Efficacy

  • J Med Chem. 2021 Oct 14;64(19):14513-14525. doi: 10.1021/acs.jmedchem.1c01036.
Pei-Ru Jin 1,  Yen-Nhi Ngoc Ta 1,  I-Ting Chen 2,  Yan-Ning Yu 1,  Hsin Tzu Hsieh 1,  Van-Anh Thi Nguyen 1,  Shang-Ying Hsieh 1,  Tiffaney Hsia 1 3,  Hao Liu 4,  Chan-Wei Hsu 5,  Jeng-Liang Han 2 5,  Yunching Chen 1
Affiliations

Affiliations

  • 1 Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 30013, Taiwan.
  • 2 Department of Chemistry, National Chung Hsing University, 145 Xingda Rd., South District, Taichung City 40227, Taiwan.
  • 3 Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
  • 4 Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, United States.
  • 5 Department of Chemistry, Chung Yuan Christian University, Taoyuan City 320314, Taiwan.
PMID: 34558909 DOI: 10.1021/acs.jmedchem.1c01036
Abstract

Autophagy is upregulated in response to metabolic stress, a hypoxic tumor microenvironment, and therapeutic stress in various cancers and mediates tumor progression and resistance to Cancer therapy. Herein, we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited Autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced Apoptosis but also blocked Autophagy in HCC cells, as indicated by the increased expression of LC3-II and p62, inhibition of autophagosome-lysosome fusion, and suppression of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve its solubility and efficacy, we encapsulated C1 into PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA) nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented distant metastasis while maintaining a desirable safety profile. Our findings demonstrate that C1 combines Autophagy modulation and Apoptosis induction in a single molecule, making it a promising therapeutic option for HCC.

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