Paeonol induces antitumor effects in hepatocellular carcinoma cells through survivin via the cyclooxygenase-2/prostaglandin E2 signaling pathway

Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most life-threatening malignancies worldwide due to the lack of significant improvement in therapeutic methods. This study aimed to unravel the effects of paeonol, the main active component of Paeonia suffruticosa, on survivin, a key molecule in tumorigenesis, and elucidate the mechanisms by which paeonol exerts antineoplastic effects in human HCC cells.Methods: Immunohistochemistry (IHC) was used to study the expression levels of survivin and cyclooxygenase-2 (COX-2) in 57 human HCC tissue samples. Human HCC cell lines (HepG2 and SMMC-7721) were treated with prostaglandin E2 (PGE2). Subsequently, the cells were treated with paeonol and NS-398, and the expression levels of survivin, COX-2, and PGE2 were evaluated by Western blotting and enzyme-linked immunosorbent assay (ELISA), respectively. Fluorescence-activated cell sorting (FACS) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed to analyze cell proliferation and apoptosis.Results: Survivin was expressed in 47 of 57 human HCC tissue samples, as observed by IHC, and its expression was correlated with COX-2 activity. Furthermore, Western blotting showed that the expression of survivin was increased in HepG2 and SMMC-7721 cells treated with PGE2, the biosynthesis of which is mainly regulated by COX-2. Interestingly, FACS and TUNEL staining demonstrated that paeonol significantly inhibited the proliferation of HepG2 and SMMC-7721 cells and induced apoptosis, concomitant with the downregulation of survivin. The levels of COX-2 and PGE2 were also reduced by paeonol, as confirmed by Western blotting and ELISA, respectively. To determine the mechanism by which paeonol inhibited survivin in HCC cells the effects of COX-2 expression on surviving were studied. Treatment with the COX-2 selective inhibitor NS398 effectively decreased the levels of PGE2 and survivin, inducing apoptosis in a manner similar to that of paeonol. Survivin expression was increased by PGE2 treatment but was blocked by paeonol, which suggests that paeonol inhibits survivin by inhibiting the COX-2/PGE2 signaling pathway. Conclusions:To the best of our knowledge, this is the first study to demonstrate that paeonol can exert antitumor effects on HCC cells by targeting survivin via the COX-2/PGE2 signaling pathway. Paeonol could therefore be considered as a potential therapeutic candidate for HCC.

Pharmacological effects and mechanisms of paeonol on antitumor and prevention of side effects of cancer therapy

“…In particular, uncontrolled cell proliferation is a hallmark of cancer, and targeting this process is essential to controlling tumor progression ( Loftus et al, 2022 ). There is considerable evidence to suggest that paeonol exhibits inhibitory effects on cancer cell growth and proliferation in a variety of cell lines, including cervix cancer HeLa cells ( Du et al, 2022 ), human bladder cancer T24 and 5,637 cells ( Zhang et al, 2021a ), non-small-cell lung cancer A549 cells, hepatocellular carcinoma Hep3B, Huh-7, BEL-7404, SMMC-7721, MHCC97-H cells ( Chunhu et al, 2008 ; Cai et al, 2020 ; Liu and Zhang, 2020 ), colorectal cancer HT-29 cells ( Ye et al, 2009 ), pancreatic cancer Panc-1, Capan-1 cells ( Cheng et al, 2020 ), osteosarcoma Saos-2, MG-63 cells ( Zhou et al, 2020 ), ovarian cancer A2780, SKOV3, OVCAR-3 cells ( Zhou et al, 2017 ; Gao et al, 2019 ), gastric cancer SGC-7901, BGC823, HGC-27 cells ( Lyu et al, 2017 ; Fu et al, 2018 ), breast cancer MDA-MB-231 cells ( Saahene et al, 2018 ), prostate cancer DU145, PC-3 cells ( Xu et al, 2017 ), fibrosarcoma HT-1080 cells, esophageal cancer SEG-1, Eca-109 cells ( Sun et al, 2008 ), glioma U87MG cells, U251 cells ( Hao et al, 2023 ). These data indicate that paeonol has broad-spectrum antitumor properties, inhibiting tumor cell proliferation in a dose/time-dependent manner in various tumor cell lines.…”

Paeonia × suffruticosa (Moutan Peony)—A Review of the Chemical Composition, Traditional and Professional Use in Medicine, Position in Cosmetics Industries, and Biotechnological Studies

“…Currently, valuable scientific publications focus on the increasing pharmacological action of the extract, mainly from Moutan cortex , as well as the compounds present in it. They include research on, among others, antioxidant, anti-inflammatory, cytoprotective, anti-cancer and neuroprotective activities [ 19 , 20 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. Other studies also include activities which are important due to modern civilization’s diseases, such as cardioprotective and anti-atherosclerotic, anti-diabetic and hepatoprotective effects [ 21 , 34 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82...…”

“…Peonol significantly inhibited the proliferation of human liver cancer cell line (HepG2) and human hepatocarcinoma cell line (SMMC-7721) and induced apoptosis, concomitant with the down-regulation of survival. The levels of COX-2 and PGE2 were also reduced by paeonol [ 55 ] ( Table 3 ).…”