Cucurbitacin C suppresses the progression of pancreatic ductal adenocarcinoma via inhibition of the cGMP-PKG-VASP axis

Dongchao Xu; Ajuan Liu; Qiang Liu; Hongchen Zhang; Mengyao Tian; Ying Bian; Xiaofeng Zhang; Meidan Ying; Hongzhang Shen

doi:10.1016/j.bcp.2023.115810

Cucurbitacin C suppresses the progression of pancreatic ductal adenocarcinoma via inhibition of the cGMP-PKG-VASP axis

Biochem Pharmacol. 2023 Nov:217:115810. doi: 10.1016/j.bcp.2023.115810. Epub 2023 Sep 17.

Authors

Dongchao Xu¹, Ajuan Liu², Qiang Liu³, Hongchen Zhang³, Mengyao Tian⁴, Ying Bian⁴, Xiaofeng Zhang⁵, Meidan Ying⁶, Hongzhang Shen⁷

Affiliations

¹ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310000, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310000, China.
² Hangzhou Medical College, Hangzhou 311300, China.
³ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310000, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310000, China.
⁴ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
⁵ Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310000, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310000, China. Electronic address: zxf837@tom.com.
⁶ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: mying@zju.edu.cn.
⁷ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Hangzhou Institute of Digestive Diseases, Hangzhou 310000, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou 310000, China. Electronic address: shenhongzhang@zju.edu.cn.

PMID: 37717690
DOI: 10.1016/j.bcp.2023.115810

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating diseases; it has a considerably poor prognosis and may become the second most lethal malignancy in the next 10 years. Chemotherapeutic resistance is common in PDAC; thus, it is necessary to exploit effective alternative drugs. In recent years, traditional folk medicines and their extracts have shown great potential in cancer treatment. The seed of Lagenaria siceraria (Molina) Standl. is a traditional medicine in Asia. Because of its analgesic effects and ability to reduce swelling, it is often used as an adjuvant treatment for abdominal tumors. Cucurbitacin compounds are extracts abundant in Lagenaria siceraria (Molina) Standl. Here, we found that cucurbitacin C (CuC), a member of the cucurbitacin family, has apparent anti-PDAC therapeutic properties. CuC decreased the viability and suppressed the proliferation of PDAC cells in a time- and dose-dependent manner. Further studies revealed that CuC inhibited cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT). In addition, G2/M arrest was induced, and the apoptotic pathway was activated. Transcriptomic and bioinformatic analyses showed that CuC inhibited the cGMP-PKG-VASP axis, increasing the content of cGMP to restore tumor characteristics. The antitumor activity of CuC in vivo was verified through animal experiments, and no obvious side effects were observed. Overall, our study indicates a candidate therapeutic compound for PDAC that is worthy of further development.

Keywords: Cancer progression; Cucurbitacin C; Pancreatic ductal adenocarcinoma; cGMP-PKG-VASP axis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Carcinoma, Pancreatic Ductal* / metabolism
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cucurbitacins / pharmacology
Epithelial-Mesenchymal Transition
G2 Phase Cell Cycle Checkpoints
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms* / metabolism

Substances

cucurbitacin C
Cucurbitacins