Erianin inhibits human lung cancer cell growth via PI3K/Akt/mTOR pathway in vitro and in vivo

Abstract

Erianin is a small‐molecule compound that is isolated from Dendrobium chrysotoxum Lindl. In recent years, it has been found to have evident antitumor activity in various cancers, such as bladder cancer, cervical cancer, and nasopharyngeal carcinoma. In this study, we assessed the effect of erianin on lung cancer in terms of cell growth inhibition and the related mechanism. First, erianin at a concentration of less than 1 nmol/L exhibited cytotoxicity in H1975, A549, LLC lung cancer cells, did not cause marked growth inhibition in normal lung and kidney cells, induced obvious apoptosis and G2/M phase arrest of cells, and inhibited the migration and invasion of lung cancer cells in vitro. Second, in a mouse xenograft model of lewis lung cancer (LLC), oral administration of erianin (50, 35, and 10 mg kg−1 day−1 for 12 days) substantially inhibited nodule growth, reduced the fluorescence counts of lewis cells and the percentage vascularity of tumor tissues, increased the number of apoptotic tumor cells, the thymus indices, up‐regulated the levels of interleukin (IL)‐2 and tumor necrosis factor‐α (TNF‐α), decreased IL‐10 levels and the spleen index, and enhanced immune function. Lastly, the possible targets of erianin were determined by molecular docking and verified via western blot assay. The results indicated that erianin may achieve the above effects via inhibiting the phosphoinositide 3‐kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in vitro and vivo. Taken together, the results showed that erianin had obvious antitumor effects via inhibiting the PI3K/Akt/mTOR pathway in vitro and vivo and may have potential clinical value for the treatment of lung cancer.

Anticancer Activity of Erianin: Cancer-Specific Target Prediction Based on Network Pharmacology

“…To better assess the binding ability of erianin to its potential targets, molecular docking was subsequently performed using Discovery Studio. Indeed, as is shown in Figure 4A , erianin exhibits high binding affinity to PI3K protein with the -CDOCKER energy of 20.5685 kcal/mole via sites of Trp292, Asp788, Arg690, His295, Trp201, Lys298, Leu864, and Glu852, indicating the high potential of PIK3CA as a target of erianin, which is consistent with the previously reported study ( Zhang et al, 2021a ). Besides, erianin also shows high binding affinity to RET and KIT in theory with the -CDOCKER energy of 28.8041 kcal/mole and 26.1821 kcal/mole, respectively, as shown in Figure 4B and Figure 5A .…”

“…In addition to the anti-angiogenesis activity, induction of apoptosis and cell cycle arrest, and modulation of immune inflammatory response, some other signaling pathways were also involved in the anticancer action of erianin. As is reported by Zhang et al (2021a) , erianin can inhibit the growth of human lung cancer cells by affecting the PI3K/AKT/mTOR signaling pathway. In their study, they firstly explored the possible targets of erianin by molecular docking and then verified those targets via western blotting.…”

“…Actually, erianin has been reported to be able to downregulate the phosphorylation of JAK2 and STAT3 in 2LL cells, and thus inhibit the expression of several inflammatory mediators, such as COX-2 (cyclooxygenase-2), HIF-1α, and IL-6 (interleukin-6) ( Su et al, 2017 ). Moreover, PIK3CA, as one of most important regulatory molecules involved in PI3K–AKT and MAPK signaling pathways, has been frequently identified as a target of erianin in various cancers ( Yang et al, 2020a ; Wang et al, 2021 ; Xu et al, 2021 ; Zhang et al, 2021a ). According to KEGG pathway analysis, KIT, ERBB2, FLT3, PIK3CA, and RET are enriched in central carbon metabolism in cancer, while ABL1, CHEK2, and CCND1 are highly related to the cell cycle process, both of which are relatively less explored.…”

Erianin, a promising agent in the treatment of glioblastoma multiforme triggers apoptosis in U373 and A172 glioblastoma cells

“…Cell migration plays a key role in many processes including embryological development, immunity, tissue formation and cancer progression [25]. In previous studies, the effects of erianin on cell migration and invasion were shown in different cancer cells [6,8,11,13,26], and using wound healing and transwell assays, erianin suppresses lung cancer cell migration [11], while erianin suppressed H1975 lung cancer cell metastasis [27]. In another study, Ecust004, a drug candidate optimized from the structure-activity relationship studies of sulfamate derivatives of erianin and CA4, was shown to suppress breast cancer cell invasion and migration [22].…”

Therapeutic benefits of Salvia species: A focus on cancer and viral infection

“…In PC-3 cells, RE was shown to inhibit cellular migration by 48% through the reduction in mRNA expression of AKT and mTOR by 27% and 40%, respectively, and their phosphorylation by 70% and 65%, respectively [ 27 ], suggesting that RE inhibit the migration of the cancer cell by modulating PI3K/AKT/mTOR signaling pathway [ 85 ]. This is because PI3K/AKT/mTOR signaling pathway has been implicated in development and progression of many cancer cells [ 86 , 87 , 88 , 89 ], making it a good target for new anticancer agents in pipeline such as coptisin [ 90 ], zingerone [ 91 ], mangiferin [ 92 ], erianin [ 93 ], melatonin [ 94 , 95 ] and rapamycin [ 96 ]. A similar result, although not compared with any reference anticancer agent, was reported in another in vitro study, where chrysin, at 40 μM (less than the toxic dose of 80 μM) elevated TET1 expression in MKN-45 cells by 61.54%, thereby reducing the cells’ migration and invasion by about 44 and 72%, respectively [ 80 ].…”