<p>ISL Induces Apoptosis and Autophagy in Hepatocellular Carcinoma via Downregulation of PI3K/AKT/mTOR Pathway in vivo and in vitro</p>

Abstract

Aims: Isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, has previously been reported to have anti-tumor effects in vivo and in vitro. However, the mechanisms whereby ISL exerts its anticancer effects remain poorly understood in hepatocellular carcinoma (HCC). Purpose: In the present study, we investigated the anticancer efficacy and associated mechanisms of ISL in HCC MHCC97-H and SMMC7721 cells. Results: We found that ISL inhibited cell viability and proliferation and induced apoptosis in a dose-and time-dependent manner in liver cancer lines. Furthermore, ISL could activate autophagy in HCC cells, and the autophagy inhibitor HCQ enhances ISL-induced apoptosis in HCC cells. Additionally, ISL induced apoptosis and autophagy through inhibition of the PI3K/Akt/mTOR pathway. Most importantly, in a xenograft tumor model in nude mice, data showed that the administration of ISL decreased tumor growth and concurrently promoted the expression of LC3-II and cleaved-caspase-3. Interestingly, we found that ISL inhibits mTOR by docking onto the ATP-binding pocket of mTOR (ie, it competes with ATP). We thus suggest that mTOR is a potential target for ISL inhibition of hepatocellular carcinoma development, which could be of interest for future investigations. Conclusion: Taken together, the results reveal that ISL effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction in vivo and in vitro, probably via the PI3K/Akt/mTOR pathway. ISL may be a potential therapeutic agent for hepatocellular carcinoma.

Programmed Cell Death Alterations Mediated by Synthetic Indole Chalcone Resulted in Cell Cycle Arrest, DNA Damage, Apoptosis and Signaling Pathway Modulations in Breast Cancer Model

“…These results indicate, at least partially, that ZK-CH-11d-induced autophagy in BC cells is mediated via the activation of AMPK with simultaneous inhibition of PI3K/Akt/mTOR pathway. This finding is in line with previous reports [ 90 , 91 ]. Moreover, inhibitory effect of ZK-CH-11d on PI3K/Akt/mTOR pathway can be also associated with PTEN, a negative regulator of PI3K/Akt signalling [ 92 ].…”

Natural products targeting macroautophagy signaling in hepatocellular carcinoma therapy: Recent evidence and perspectives

“…In the future, with the deepening of scientific research, we expect that the potential value of autophagy modulators and natural products in liver cancer treatment will be On the other hand, excessive induction of autophagy can also lead to autophagic cell death of HCC cells. In the current study, we found that Isoliquiritigenin could promote autophagy in MHCC97-H and SMMC7721 cells by regulating PI3K/AKT/mTOR signaling pathway even in the same pathway (Song et al, 2020). However, sheng et al…”

Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones

“…These effects were associated with decreased expression of Akt [ 205 ]. Recently, Song and co-workers [ 206 ] studied antiproliferative effect of ISL in hepatocellular carcinoma. Similarly, to calomelanone, ISL induced death of cancer cells via initiation of both apoptosis and autophagy.…”