Gypenoside L Inhibits Proliferation of Liver and Esophageal Cancer Cells by Inducing Senescence

Abstract

Senescence is an irreversible state of cell cycle arrest that can be triggered by multiple stimuli, such as oxygen reactive species and DNA damage. Growing evidence has proven that senescence is a tumor-suppressive approach in cancer treatment. Therefore, developing novel agents that modulate senescence may be an alternative strategy against cancer. In our study, we investigated the inhibitory effect of gypenoside L (Gyp-L), a saponin isolated from Gynostemma pentaphyllum, on cancer cell growth. We found that Gyp-L increased the SA-β-galactosidase activity, promoted the production of senescence-associated secretory cytokines, and inhibited cell proliferation of human liver and esophageal cancer cells. Moreover, Gyp-L caused cell cycle arrest at S phase, and activated senescence-related cell cycle inhibitor proteins (p21 and p27) and their upstream regulators. In addition, Gyp-L activated p38 and ERK MAPK pathways and NF-κB pathway to induce senescence. Consistently, adding chemical inhibitors efficiently counteracted the Gyp-L-mediated senescence, growth inhibition, and cell cycle arrest in cancer cells. Furthermore, treatment with Gyp-L, enhanced the cytotoxicity of clinic therapeutic drugs, including 5-fluorouracil and cisplatin, on cancer cells. Overall, these results indicate that Gyp-L inhibits proliferation of cancer cells by inducing senescence and renders cancer cells more sensitive to chemotherapy.

Progress in the Medicinal Value, Bioactive Compounds, and Pharmacological Activities of Gynostemma pentaphyllum

“…However, gypenoside L could render cancer cells more sensitive to chemotherapy such as cisplatin by impairing the protective autophagy. Based on this, gypenoside L could be explored as a promising agent for solving the problem of resistance [ 16 ].…”

Targeting senescent cells and tumor therapy (Review)

“…ZEHUA WANG 1,2* , JIANWEN GAO 3-5* , HAIOU LIU 1,2 , YUKO OHNO 3 and cONGJIAN XU 1,2,6 1 Obstetrics and Gynecology Hospital of Fudan University; 2 Shanghai Key Laboratory of Female Reproductive Endocrine Related diseases, Shanghai 200011, P.R. china; 3 department of Mathematical Health Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; 4 School of Medical Engineering, Ma'anshan University, Ma'anshan, Anhui 243100; 5 Major of Biotechnological Pharmaceutics, Shanghai Pharmaceutical School, Shanghai 200135; 6 department of Obstetrics and Gynecology of Shanghai Medical School, Fudan University, Shanghai 200032, P.R. china Cellular morphological changes.…”

“…Cell senescence plays important roles in non-disease-related physiological processes, including embryo development, wound healing, tissue repair and aging ( 1 ). A large number of previously published studies have demonstrated that cell senescence plays an important role in the inhibition of potential cancer cell proliferation pathways ( 2 - 4 ). However, as the detailed scientific knowledge in this field continues to expand, it has been demonstrated that senescent cells also secrete a variety of cytokines, chemokines, matrix-remodeling proteases and growth factors to form the senescence-associated secretory phenotype (SASP), which is a 'double-edged sword' in that it may either inhibit or promote tumor formation ( 5 ).…”

Phlorizin from sweet tea inhibits the progress of esophageal cancer by antagonizing the JAK2/STAT3 signaling pathway

“…Natural products are important resources for anticancer drugs ( 11 , 12 ), such as gypenoside L and matrine. Studies have demonstrated that gypenoside L inhibited the proliferation of esophageal cancer cells and enhanced the sensitivity of them to chemotherapy ( 13 ), and matrine increased the inhibition rate of cell proliferation by inducing cell autophagy ( 14 ). Therefore, there is an urgent requirement to develop natural medicine with high efficiency and minimal side effects to improve the treatment of esophageal cancer and improve population health.…”