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

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.

Linderalactone Suppresses Pancreatic Cancer Development In Vitro and In Vivo via Negatively Regulating PI3K/AKT Signaling Pathway.

Linderalactone is one of the main extracts of Linderae Radix, which is widely used in traditional Chinese medicine. There have been few studies on the antitumor effect of linderalactone in the past. In this study, we explored the anti-pancreatic cancer activity of linderalactone in vitro and in vivo. The results showed that linderalactone inhibited the proliferation of pancreatic cancer cells in a time- and dose-dependent manner. Cell migration and invasion were significantly inhibited by linderalactone. The cell cycle was arrested in the G2/M phase, and the expression levels of cell cycle-associated proteins changed significantly with linderalactone treatment. In addition, linderalactone induced cell apoptosis and altered the expression of apoptotic markers, such as caspase 3 and PARP1. Mechanistically, linderalactone suppressed the PI3K/AKT signaling pathway by downregulating the phosphorylation of PI3K and AKT. The xenograft study results were consistent with the in vitro results, and there was no obvious chemical toxicity. Thus, our research demonstrated that linderalactone exhibits antitumor activity against pancreatic cancer and may be developed as a potential anti-pancreatic cancer agent in the future.