Sodium cantharidinate, a novel anti-pancreatic cancer agent that activates functional p53

Abstract

Despite the use of many types of chemotherapies for pancreatic cancer, optimal efficacy has not been obtained so far. Pancreatic cancer shows a high incidence of TP53 mutations, inactivating its tumor suppressor activity. In this study, we identified sodium cantharidinate as a novel, potential anti-pancreatic cancer agent that activates p53 function. Sodium cantharidinate reduced the viability of pancreatic cancer cells, including the human primary pancreatic cancer cells, PANC-1, AsPC-1, SW1990 and BXPC-3, in a dose-dependent manner. Sodium cantharidinate induced apoptosis and DNA damage of pancreatic cancer cells. Furthermore, proteome-wide sequencing analysis detected a marked perturbation in p53 signaling pathway on PANC-1 cells upon sodium cantharidinate. Consistent with the previous results, sodium cantharidinate treatment decreased Bcl-2 and mitochondrial cytochrome-c protein expression, as well as phosphorylation of MDM2; meanwhile, it increased the levels of cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP, Bax, and phosphorylated p53, thus inducing the apoptosis of pancreatic cancer cells. The p53activating effect of sodium cantharidinate was strongly abrogated by treatment with TP53-targeting shRNA. Moreover, sodium cantharidinate inhibited neoplasm growth via the JAK2-STAT3 pathway, which was inhibited by shRNA-TP53 and triggered by combination with gemcitabine. Combination therapy indicated that sodium cantharidinate and gemcitabine synergistically reduced ex vivo and in vivo growth of pancreatic neoplasm. Further docking studies revealed the different binding fates of sodium cantharidinate to activate wild-type p53 function. Thus, sodium cantharidinate could be a potential agent with promising anti-pancreatic cancer efficacy.

Rare Carbon-Bridged Citrinin Dimers from the Starfish-Derived Symbiotic Fungus Penicillium sp. GGF16-1-2

“…The analysis results of the PPI indicated that CASP3 has the most degree scores, which means CASP3 could be the essential protein for 1 ( Figure 5 A,B). We verified it via a Western blot experiment in vitro and found that 1 could affect CASP3 expression ( Figure 5 C), which reportedly plays a crucial role in the cell apoptosis pathway [ 33 , 34 , 35 ]. Therefore, we hypothesized that 1 might promote BXPC-3 apoptosis by affecting the activation of CASP3.…”

Norbornene and Related Structures as Scaffolds in the Search for New Cancer Treatments

“…Among all the derivatizations, salt formation has been one of the most interesting due its simplicity. For example, sodium cantharidinate (Figure 9, 9h) induced apoptosis and DNA fragmentation of pancreatic cancer cells (PANC-1) with perturbation in p53 signaling pathway [124]. Kian's group tested this salt against breast cancer and detected apoptosis and cell cycle arrest with possible implication of p53 [125].…”

Sodium cantharidate promotes autophagy in breast cancer cells by inhibiting the PI3K–Akt–mTOR signaling pathway

“…Furthermore, SCA can induce HepG2 cell apoptosis via the LC3 autophagy pathway ( Tao et al, 2017 ). Moreover, in pancreatic cancer cells, SCA exerts antitumor effects by activating p53 ( Liu et al, 2021 ). However, the application of SCA for breast cancer treatment has not yet been reported.…”