Brevilin A Isolated from Centipeda minima Induces Apoptosis in Human Gastric Cancer Cells via an Extrinsic Apoptotic Signaling Pathway

Abstract

Brevilin A, which has anticancer activities against a range of cancers, is an abundant constituent of the medicinal herb Centipeda minima (L.) A. Braun & Asch, which has also been reported to have anticancer activity against breast cancer cells. However, the anticancer activities of C. minima and brevilin A against human gastric cancer have yet to be reported. In this study, we aimed to evaluate the cytotoxicity and molecular basis underlying the anticancer activities of extracts of C. minima (CMX) and brevilin A against human gastric cancer (AGS) cells. We deduced the potential targets and mechanisms underlying the anticancer activity of brevilin A based on a network pharmacology approach. CCND1, CDK4, and BCL2L1 were identified as the key anticancer genes targeted by brevilin A. Cytotoxicity analyses revealed that CMX and brevilin A reduced the viability of AGS cells to levels below 50% (9.73 ± 1.29 µg/mL and 54.69 ± 1.38 μM, respectively). Furthermore, Hoechst 33342, annexin V, and propidium iodide staining and western blot analyses revealed that CMX and brevilin A promoted a significant induction of apoptotic cell death by upregulating the expression of cleaved caspase-8 and cleaved caspase-3 and reducing the ratio of Bax to Bcl-2, which is partially consistent with the findings of our network pharmacology analysis. Collectively, our observations indicate that CMX and brevilin A are novel sources of herbal medicine with potential utility as effective agents for the treatment of gastric cancer.

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

“…Brevilin A (BA), a natural sesquiterpene lactone, is purified from Centipeda minima herb, a Traditional Chinese Medicine (TCM) initially used to relieve stuffy nose, asthma, and cough [ 3 ]. Recent studies have revealed the great efficacy of BA on antitumor activities, particularly those of the breast cancer [ 3 , 4 ], gastric cancer [ 5 ], colon carcinoma [ 6 ], lung cancer [ 7 , 8 ], glioblastoma [ 9 ], melanoma [ 10 ], multiple myeloma [ 11 ], and nasopharyngeal carcinoma [ 12 ]. Specifically, BA inhibits proliferation, migration, and invasion, in part, through suppressing signaling pathways, including JAK2/STAT3 and PI3K/AKT/mTOR [ 3 , 4 , 6 , 7 , 13 ].…”

Sesquiterpene lactones as emerging biomolecules to cease cancer by targeting apoptosis

“…The results of the in-vivo study indicated the growth-inhibitory activity of Brevilin A by triggering apoptosis and autophagy in tumor tissues. Lee et al (2022) studied the effects of brevilin A on human gastric cancer (AGS) cells. They observed that CMX and brevilin A triggered apoptotic cell death AGS cells by increasing the activated forms of caspase 8 and caspase 3, reducing Bcl-2, and inducing the expression of Bax.…”

Natural products targeting signaling pathways associated with regulated cell death in gastric cancer: Recent advances and perspectives

“…Yan and coworkers found that costunolide triggered intrinsic mitochondria‐dependent apoptosis through elevating puma and Bax expressions and down‐regulating Bcl‐2 in BGC‐823 cells (Yan, Xu, et al, 2019b). Similarly, brevilin A, an active constituent obtained in Centipeda minima (L.), showed to induce mitochondria‐dependent apoptosis via negatively regulation of Bcl‐2 in AGS cells (Lee et al, 2022). Moreover, Wang and colleagues recently reported that hydroxysafflor yellow B, a bioactive ingredient from the petals of the safflower, caused mitochondria‐dependent apoptosis by promoting Bax expression and down‐regulating Bcl‐2 (Wang, Wang, et al, 2022a).…”