Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway

Abstract

BackgroundGastric cancer is one of most commonly diagnosed cancers and causes significant mortality worldwide. In this study, the antiproliferative and anticancer effects of Phloretin were evaluated against gastric cancer cell lines.Material/MethodsMTT assay was used to assess the proliferation rate of gastric cancer cells. DAPI and annexin V/PI were used for detection of apoptotic cell death. Cell invasion was investigated by Transwell assays and the expression of the proteins was estimated by immunoblotting.ResultsThe results revealed that Phloretin exerts anticancer effects on all the gastric cancer cell lines used in this study. However, the anticancer effects were more significant (p<0.05) on the AGS cell line. Further, the effect of Phloretin on the viability of normal GES-1 cells was minimal. Apoptosis assays showed that Phloretin triggers apoptotic cell death in AGS gastric cancer cells. Phloretin could also cause the arrest of the AGS gastric cancer cells in the G2/M phase of the cell cycle and suppress their ability to migrate. Western blotting analysis revealed that Phloretin significantly decreased the expression of p-JNK and p-38. However, comparatively lower effects were observed on the expression of JNK and P38.ConclusionsWe showed that Phloretin is an important molecule for the treatment of gastric cancer.

Biochemical Basis of Anti-Cancer-Effects of Phloretin—A Natural Dihydrochalcone

“…Park et al [14] reported that the induction of apoptosis in human colon cancer (HT-29) cells upon treatment with phloretin was associated with increased expression of Bax and release of cytochrome c and Smac/DIABLO in the cytosol, thereby resulting in the cleavage of caspase-8, -9, -7, and -3 and poly(ADP-ribose) polymerase (PARP) [14]. A recent study demonstrated that phloretin induced apoptosis selectively in human gastric cancer cell lines (MGC80-3, BGC-823, SGC-7901, SNU-1, SNU-5, RF-1 and AGS), with IC 50 values ranging from 8 to 32 µM without affecting the growth of normal gastric epithelial cells [39]. Incubation of AGS cells with phloretin reduced the colony formation in a concentration-dependent manner by arresting cell cycle at the G2/M phase.…”

“…Incubation of AGS cells with phloretin reduced the colony formation in a concentration-dependent manner by arresting cell cycle at the G2/M phase. Moreover, the induction of apoptosis in AGS cells by phloretin was associated with the increase in Bax expression, inhibition of Bcl-2 levels and decrease in the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAP kinase [39]. In contrast, the activation of JNK and p38 MAP kinase has been attributed to phloretin-induced caspase-3 cleavage in H- ras -transformed human mammary epithelial cells (H- ras -MCF-10A) [55].…”

“…Further studies are required to confirm the effects of phloretin on cadherin levels and its impact on tumor cell migration. Phloretin also attenuated the invasion of human gastric cancer (AGS) cells by blocking the phosphorylation of MAP kinases [39].…”

Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment

“…Phloretin increased the efficacy of HSP70 penetration and thus its anticancer activity in B16 mouse melanoma cells and K-562 human erythroblasts [27]. Phloretin showed anticancer activity in several human cancer cell lines, including lung (A549), liver (HepG2), colon (HT-29) [28], gastric (AGS) [29], esophageal (EC-109) [30], breast (MDA-MB-231) [31], prostate (LNCaP) [32] and glioblastoma cells [33]. Phloretin has a cancer preventative role by its activity in reducing oxidative DNA damage, as observed in human colon cancer cell lines (Caco-2 and HT-29) [34].…”

A Newfangled Coordinated Ruthenium Phloretin Complex Reprogramming Breast Cancer Microenvironment Interceded by Modulation of PI3K/Akt/Mtor/VEGF Pathway and Modifying The Antioxidant Status Correlated With Intensified Apoptotic Events.

“…Phloretin also has an inhibitory role on dextran sulfate sodium-induced ulcerative colitis in mice by altering nuclear factor-κB, toll-like receptor 4 and PPARγ pathways (16). In addition, phloretin possesses diverse pharmaco-therapeutic effects on human malignancies, including the suppression of oral squamous cell carcinoma by modulating the glucose uptake (17), apoptosis in human gastric cancer by arresting the cell cycle of G2/M phase, suppression of cell invasion by diminution of JNK activity (18), attenuation of triple-negative breast cancer cell proliferation and migration (19) and promote apoptosis in human esophageal cancer (20). A very recent literature suggested that phloretin loaded chitosan nanoparticles augments the mitochondrial mediated intrinsic apoptosis in human oral cancer cells (21).…”