Novel norditerpene-phenanthrenes from Selaginella effusa inhibit T24 cell proliferation via blockade of the TRPV1/ STAT3/NF-κB pathway

Ten novel norditerpene-phenanthrenes (1-10) and two new analogs (11-12) were isolated from Selaginella effusa. Their structures and absolute configuration were established by HRESIMS; IR, UV, 1D and 2D NMR spectroscopy; X-ray crystallography; and ECD. The antiproliferative effects of these compounds were evaluated in T24 cells via the MTT method and compound 1 exhibited the greatest antitumor activity, with an IC₅₀ value of 3.21 μM. A mechanistic study revealed that compound 1 inhibited not only T24 cell proliferation but also the TRPV1 ionchannel. Mechanistically, compound 1 induces cell damage and cell cycle arrest by downregulating PARP1, CDK2 and Cyclin E1 by modulating STAT3-mediated signaling pathways in T24 cells. Compound 1 also regulates NF-κB-mediated signaling in T24 cells, decreases ther mitochondrial membrane potential, and increases the level of mitochondrial reactive oxygen species, thereby inducing cell apoptosis. In addition, compound 1 also showed the potential to inhibit MMP-9 and N-cadherin, thereby suppressing cancer cell proliferation and migration. These findings suggest that compound 1 might be a potential lead compound for chemotherapeutic development.