Apigenin induces apoptosis by regulating Akt and MAPK pathways in human melanoma cell A375SM

Abstract

apigenin, an aromatic compound, exhibits antioxidant, anti-inflammatory and anti-viral effects. The present study aimed to investigate the effects of apigenin on cell proliferation and apoptosis of human melanoma cells A375P and A375SM. Therefore, melanoma cells were treated with apigenin to determine its anti-proliferative and survival effects, using wound healing and MTT assays. The results revealed that melanoma cell viability was decreased in a dose-dependent manner. Furthermore, chromatin condensation, indicating apoptosis, was significantly increased in a dose-dependent manner, as demonstrated by DAPI staining. In addition, increased apoptosis rate following treatment with apigenin was confirmed by Annexin V-propidium iodide staining. The changes in the expression levels of apoptosis-related proteins in A375P and A375SM melanoma cells were subsequently detected using western blot analysis. The results demonstrated that the protein expression levels of Bcl-2 were decreased, whereas those of Bax, cleaved poly ADP-ribose polymerase, cleaved caspase-9 and p53 were upregulated in a dose-dependent manner in apigenin-treated cells compared with those noted in untreated cells. In addition, in apigenin-treated A375P cells, phosphorylated (p)-p38 was upregulated and p-extracellular signal-regulated kinase (ERK), p-c-Jun N-terminal kinase (JNK) and p-protein kinase B (Akt) were downregulated. However, in A375SM cells, apigenin treatment increased pERK and p-JNK and decreased p-p38 and p-Akt protein expression levels. Subsequently, the inhibitory effect of apigenin on tumor growth was investigated in vivo. Tumor volume was significantly reduced in the 25 and 50 mg/kg apigenin-treated groups compared with the control group. Additionally, a TUNEL assay was performed to detect apoptotic cells. Immunohistochemical staining also revealed elevated pERK expression in the apigenin-treated group compared with the control group. Overall, the findings of the present study indicated that apigenin attenuated the growth of A375SM melanoma cells by inducing apoptosis via regulating the Akt and mitogen-activated protein kinase signaling pathways.

Bioengineering of Genetically Encoded Gene Promoter Repressed by the Flavonoid Apigenin for Constructing Intracellular Sensor for Molecular Events

“…While 100 µM is a relatively high concentration for dietary interventions and some cellular models, this concentration was selected among those found to successfully validate protein that are directly associated with apigenin in vivo [ 33 ]. Moreover, several studies have used 100 µM as part of cellular platforms [ 34 , 35 , 36 , 37 ]. Therefore, the use of 100 µM in this study is reasonable.…”

An In Vitro-In Vivo Evaluation of the Antiproliferative and Antiangiogenic Effect of Flavone Apigenin against SK-MEL-24 Human Melanoma Cell Line

“…Following the same thought, Woo et al investigated the effect of API (25, 50, 75, and 100 μ M) for 24 h on human melanoma cells (A375P and A375SM). Using in vitro assays, this research group has shown that the cell viability was decreased, and the expression of Bax, p53, PARP, and cleaved caspase-9 increased in a dose-dependent manner [ 48 ]. Using A2058 and A375 melanoma cell lines, Hasnat et al pointed out that API treatment (10, 20, and 50 μ M) inhibited the growth of melanoma cells.…”

“…Deepening the experimental line, Woo et al transplanted the A375SM human melanoma cells in nude mice which were treated intraperitoneally with API (25 and 50 mg/kg). Results showed that the tumor size and weight were significantly decreased in a dose-dependent manner in the API treated groups when compared with the control group [ 48 ]. Cao et al demonstrated the antimetastatic effect of API in vivo using C57BL/6 mice.…”

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

“…Moreover, the sensitivity of pre-transformed cells MCF-10A to apigenin is significantly higher, in order for it to be more effective as a chemopreventive drug rather than a therapeutic [ 391 , 392 ]. Apigenin has also been shown to modulate various anti-inflammatory pathways, in particular, in [ 393 ], apigenin weakened the growth of human melanoma cells A375SM, triggering apoptotic cell death by regulating the signaling pathways Akt and MAPK. The treatment of choriocarcinoma cells JAR and JEG3 with this flavonoid inhibited the progression and metastasis of the cells through regulation of the PI3K/Akt and ERK1/2 MAPK signaling pathways.…”