2. Academic Validation
  3. A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells

A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells

  • Acta Pharmacol Sin. 2020 Jun;41(6):835-842. doi: 10.1038/s41401-019-0354-1.
You-You Yan  # 1 2,  Ke-Yu Shi  # 1 2 3,  Fei Teng  # 1 2 3,  Jing Chen 3,  Jin-Xin Che 4,  Xiao-Wu Dong 4,  Neng-Ming Lin 5 6 7,  Bo Zhang 8 9
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, 310006, China.
  • 2 Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
  • 3 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China.
  • 4 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 5 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, 310006, China. lnm1013@zju.edu.cn.
  • 6 Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China. lnm1013@zju.edu.cn.
  • 7 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 311402, China. lnm1013@zju.edu.cn.
  • 8 Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, 310006, China. zhangbohzss@163.com.
  • 9 Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China. zhangbohzss@163.com.
  • # Contributed equally.
PMID: 32047260 DOI: 10.1038/s41401-019-0354-1
Abstract

Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic Cancer is unclear, and the structure-activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2'-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior Anticancer activity against human pancreatic Cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic Cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced Apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/Akt pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic Anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/Akt pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

Keywords

Mcl-1; Noxa; PI3K/AKT; human pancreatic cancer; valepotriate.

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