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Fasting, without inducing malnutrition, has been shown to have various beneficial effects, including the inhibition of tumor initiation and progression. However, prolonged fasting poses challenges for many cancer patients, particularly those in intermediate and terminal stages. Thus, there is an urgent need for the development of fasting mimetics which harness the protective effects of fasting but more suitable for patients. In this study, we first highlighted the pivotal role of silibinin in AMP‐activated protein kinase (AMPK) pathway and may serve, as a potential fasting mimetic via screening hepatoprotective drugs. Further metabolic analysis showed that silibinin inhibited the adenosine triphosphate (ATP) levels, glucose uptake and diminished glycolysis process, which further confirmed that silibinin served as a fasting mimetic. In addition, fasting synergized with silibinin, or used independently, to suppress the growth of hepatocellular carcinoma (HCC) in vivo. Mechanistically, silibinin upregulated death receptor 5 (DR5) through AMPK activation, and thus promoting extrinsic apoptosis and inhibiting HCC growth both in vitro and in vivo. Inhibition of AMPK using small interfering RNA (siRNA) or compound C, an AMPK inhibitor, significantly attenuated the upregulation of DR5 and the apoptotic response induced by silibinin. These findings suggest that silibinin holds promise as a fasting mimetic and may serve as an adjuvant drug for HCC treatment. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC), one of the most malignant human cancers in clinic, requires novel treatment. Daurisoline (DAS) is a component of traditional Chinese herb, which exhibits anti-cancer effects by autophagy inhibition and metastasis suppression. However, the effect and mechanism of DAS on ESCC remain unclear. Here, we found that DAS inhibited cell proliferation and colony formation in both human ESCC cell lines EC1 and ECA109. Mechanistically, DAS induced p21-/p27-dependent G1 phase cell cycle arrest and apoptosis in a dose-dependent manner. The induction of apoptosis by DAS was largely dependent on the activation of the transcription factor ATF4 and its downstream NOXA-dependent intrinsic and CHOP-DR5-dependent extrinsic apoptotic pathway. ATF4 activation induced by DAS was due to the generation of excessive reactive oxygen species (ROS) and the subsequent activation of endoplasmic reticulum (ER) stress through the p-eIF2 α -ATF4 signal pathway, which can be largely abrogated by N-acetylcysteine (NAC), a scavenger of ROS. Moreover, DAS treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model by up-regulating key proteins related to cell cycle arrest and apoptotic pathway. Taken together, these findings identified DAS as a novel candidate for the treatment of ESCC., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (Copyright © 2022 Shuying Yuan et al.)