Anticancer activity of caffeic acid n‑butyl ester against A431 skin carcinoma cell line occurs via induction of apoptosis and inhibition of the mTOR/PI3K/AKT signaling pathway

Abstract

Skin cancer is one of the primary causes of mortality worldwide. With an increasing frequency of skin cancers, there is an urgent requirement for the development of numerous treatment options. The present study investigated the anticancer activity of caffeic acid n-butyl ester (CAE) against the A431 skin cancer cell line. Antiproliferative effects were investigated using an MMT assay. Apoptosis was examined by DAPI and Annexin V/fluorescein isothiocyanate and propidium iodide staining. Reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and cell cycle analyses were performed via flow cytometry. Protein expression was determined by western blotting. The findings of the present study demonstrated that among a variety of cancer cell lines, CAE exhibited significant anticancer activity against the A431 skin cancer cell line with a half-maximal inhibitory concentration of 20 µM. CAE was associated with apoptosis and cell cycle arrest of A431 cells, and induced ROS-mediated alterations in MMP. In addition, CAE considerably suppressed the expression of some of the important proteins of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) cascade. The results of the present study indicated that CAE exerted anticancer effects on the A431 skin carcinoma cell line via the induction of apoptosis and suppression of the PI3K/AKT/mTOR signaling pathway. Therefore, CAE may be beneficial for the development of chemotherapy for skin cancers.

Emerging Perspective: Role of Increased ROS and Redox Imbalance in Skin Carcinogenesis

“…As a member of the flavonoid family, quercetin is excellent in strengthening the antioxidant defense via removing H 2 O 2 , O 2 •- , and • OH and has a powerful anticancer effect on skin cancer through regulating molecular mechanisms, e.g., inhibiting activation of the MAPK, PI3K-Akt/PKB, and NF- κ B signal pathways [106]. Another natural flavonoid, caffeic acid n-butyl ester (CAE), stimulates the accumulation of toxic ROS and the decrease of MMP in A431 skin cancer cells to inhibit the PI3K/AKT/mTOR signaling pathway and thus induce cancer cell apoptosis [107]. Lee et al meanwhile showed that the flavonoid Cudraflavone C was a novel natural drug for the treatment of melanoma; this drug could activate the phosphorylation of MAPKs (p38, ERK, and JNK) and increase the expression of apoptosis proteins (Bax, cytochrome c, caspase-9, and caspase-3/7) to induce the apoptosis of melanoma cells by increasing mitochondrial ROS production [108].…”

Antitumor effects of dioscin in A431 cells via adjusting ATM/p53‑mediated cell apoptosis, DNA damage and migration

“…Skin cancer is one of the most prevalent malignancies in the world, and ~20% of the population will develop skin cancer at some point during their lifetime ( 41 ). In recent years, as the specific pathogenesis of skin cancer remains unclear, and the clinical treatment of skin cancer is also limited, the incidence of skin cancer has been increasing by 3–5% per year ( 4 ).…”

Regenerative Wound Dressings for Skin Cancer

“…The antioxidant properties are generally based on its structural features, namely the hydroxyl group which neutralizes the reactive oxygen species as it acts as an electron donor, the vinyl chain and the methoxyl group which increase molecule stability, and the carboxylic group which prevents lipid peroxidation [ 92 ]. Moreover, caffeic acid acts as a chemopreventive agent by modulating inflammatory signaling [ 93 ], suppressing the rapamycin cascade signaling, inducing apoptosis [ 94 ], and altering cell cycle and caspase gene expression [ 95 ].…”