# Mechanism of Anticancer Activity of Cedrol in Epidermal Carcinoma Cells and Its Validation in 3D Artificial Skin Model

## TL;DR

This study explores how cedrol, a natural compound, fights skin cancer cells and works in a 3D skin model.

## Contribution

The study reveals cedrol's anticancer mechanisms in epidermal carcinoma cells and validates its effect in a 3D artificial skin model.

## Key findings

- Cedrol shows concentration-dependent cytotoxicity in A431 epidermoid carcinoma cells.
- Cedrol induces G0/G1 cell cycle arrest and apoptosis via intrinsic and extrinsic pathways.
- Cedrol's effect is observed in 3D epidermal carcinoma skin but not in normal 3D skin.

## Abstract

In this study, we investigated the anticancer activity of cedrol, a sesquiterpene alcohol, in the human epidermoid carcinoma cell A431 and in epidermal carcinoma 3D skin. Although various physiological activities of cedrol have been reported, the anticancer effect of cedrol in epidermal carcinoma and its molecular mechanisms still remain unclear. Cedrol exhibited significant cytotoxicity in A431 cells in a concentration-dependent manner and reduced the expression of minichromosome maintenance (MCM) proteins. To elucidate the underlying anticancer mechanisms, cell cycle and apoptosis analyses were performed. Cedrol induced dose-dependent G0/G1 phase arrest in A431 cells after 24 h of treatment, accompanied by induction of p53 and p21 and reduction of cyclin E and CDK2. After 48 h of cedrol treatment, apoptosis was observed, as demonstrated by the increase in SubG1 population and Annexin V-positive apoptotic cells using flow cytometry. Cedrol-induced apoptosis was further confirmed by increased expression of the death receptor Fas and the pro-apoptotic protein Bax, decreased expression of the anti-apoptotic protein Bcl-2, release of cytochrome c, and PARP cleavage following caspase activation, indicating apoptosis occurred via both intrinsic and extrinsic pathways. In addition, the cytotoxic effect of cedrol was also observed in an epidermal carcinoma 3D skin constructed using A431 cells, but not in a normal 3D skin constructed using HaCaT cells. Taken together, these findings suggest that cedrol may serve as a novel anticancer therapeutic candidate for epidermal carcinoma and propose that the epidermal carcinoma 3D skin model can be utilized in nonclinical trials.