Chrysin Induces Apoptosis and Autophagy in Human Melanoma Cells via the mTOR/S6K Pathway

Abstract

Chrysin is known to exert anti-inflammatory, antioxidant, and anticancer effects. The aim of this study was to investigate the anticancer effects of chrysin in the human melanoma cells A375SM and A375P. The results obtained demonstrated successful inhibition of the viability of these cells by inducing apoptosis and autophagy. This was confirmed by the level of apoptosis-related proteins: Bax and cleaved poly (ADP-ribose) polymerase both increased, and Bcl-2 decreased. Moreover, levels of LC3 and Beclin 1, both autophagy-related proteins, increased in chrysin-treated cells. Autophagic vacuoles and acidic vesicular organelles were observed in both cell lines treated with chrysin. Both cell lines showed different tendencies during chrysin-induced autophagy inhibition, indicating that autophagy has different effects depending on the cell type. In A375SM, the early autophagy inhibitor 3-methyladenine (3-MA) was unaffected; however, cell viability decreased when treated with the late autophagy inhibitor hydroxychloroquine (HCQ). In contrast, HCQ was unaffected in A375P; however, cell viability increased when treated with 3-MA. Chrysin also decreased the phosphorylation of mTOR/S6K pathway proteins, indicating that this pathway is involved in chrysin-induced apoptosis and autophagy for A375SM and A375P. However, studies to elucidate the mechanisms of autophagy and the action of chrysin in vivo are still needed.

Advancements and recent explorations of anti-cancer activity of chrysin: from molecular targets to therapeutic perspective

“…Moreover, CH has shown the propensity to obstruct cell survival signaling pathways that are often observed to be hyperactive during autophagy in cancer cells. As such, CH can compromise the normal working of PI3K/Akt and MAPK/ERK pathways (foremost therapeutic targets in cancer treatment) by suppressing mTOR expression, thus inhibiting autophagic thrust with simultaneous enhancement of apoptosis progression in cancer cells [ 13 ]. In addition, CH can also manipulate the expression and regulation of other apoptotic partner activities such as by enhancing the p53-mediated apoptosis in response to DNA damage with simultaneous inhibition of CDK2 and CDK4, forkhead box O (FOXO) pathway and HIF-1α expression.…”

Bitter Phytochemicals as Novel Candidates for Skin Disease Treatment

“…In another mouse model of atopic dermatitis, chrysin reduced serum histamine and IgE levels, inhibited the inflammatory response, and decreased mast cell infiltration [189]. Regarding skin cancer cells, chrysin inhibited cell proliferation, migration, invasion, metastasis, induced apoptosis, and reduced angiogenesis and mTOR expression while increasing caspase-3 activity [190][191][192][193][194][195][196][197]. In a mouse model of skin carcinogenesis, chrysin decreased tumor formation, volume, and number and had a stimulatory effect on the activity of certain antioxidant enzymes (e.g., SOD, GPx) [198].…”

“…TAS2R50 [43] Atopic dermatitis [167] Liver and renal toxicity [277] Amygdalin TAS2R16 [43,170] Psoriasis (amygdalin analogues) [174][175][176] Toxicity due to hydrogen cyanide (amygdalin) [173] Berberine TAS2R38 [177] TAS2R46 [178] Atopic dermatitis [179] Melanoma [181,182] Squamous cell carcinoma [180] Gut microbiota dysbiosis [278] Diarrhea [278] Chrysin TAS2R14 [132] TAS2R39 [132] Psoriasis [188] Atopic dermatitis [189] Melanoma [190][191][192][193][194][195][196][197] Alteration in hematological parameters [279] Hepatic toxicity [279] Poor bioavailability [280] Cucurbitacin B TAS2R10 [43] TAS2R14 [43] Psoriasis [199] Squamous cell carcinoma [200] Melanoma [201][202][203] Low oral bioavailability [281] Non-selective toxicity [282] Epigallocatechin gallate TAS2R14 [132,204] TAS2R31 [204] TAS...…”