Graptopetalum paraguayense (N.E.Br.) E. Walther is an herbaceous medicinal plant belonging to the Crassulaceae family and has several biological activities. Our previous research pointed out that 50% ethanolic G. paraguayense (N.E.Br.) E. Walther extract (GE50) has no mutagenic effect on the five Ames tester strains. Using Salmonella typhimurium TA102 as the test strain, GE50 has an anti-mutagenic effect and can prevent oxidative mutagenesis caused by organic peroxide (Chen et al., 2005, Chou et al., 2005). In-vitro studies have indicated that G. paraguayense (N.E.Br.) E. Walther extract is rich in polyphenols and anthocyanins, possesses antioxidative and hepatoprotective effects, and inhibits the activity of tyrosinase and angiotensin-converting enzyme (Chen et al., 2007, Chen et al., 2008, Chung et al., 2005, Huang et al., 2005). In addition, G. paraguayense can reduce oxidative stress in hypercholesterolemic patients (Lin et al., 2011). These studies showed that G. paraguayense possesses several health benefits. However, the anti-melanoma mechanisms of G. paraguayense and its molecular signaling remain unknown.

Melanoma is the most dangerous types of skin cancer. It is highly malignant and one of the main causes of deaths from skin cancer. Many reports have demonstrated that apoptosis is one of the important mechanisms leading to the death of cancer cells, and the modulated regulatory protein levels on cell cycle or apoptosis have been investigated in the melanoma cells (Hwang et al., 2020, Ng et al., 2018). In the process of cell apoptosis, the morphological changes such as DNA and nuclear condensation, DNA fragmentation, and apoptotic bodies can be observed (Zhang and Xu, 2000). Apoptosis consists of intrinsic and extrinsic pathways. The intrinsic apoptotic pathway is involved in mitochondrial membrane disruption. The extrinsic apoptotic pathway requires the death receptors to activate downstream caspases (Elmore, 2007). The initiator caspase-8 and caspase-9 are activated in response to traditional Chinese herb or phytochemicals’ stimuli, and then directly activate downstream effectors of caspase-3 (Hong and Choi, 2012, Huang et al., 2012). Liu et al. (2010) have observed that endoplasmic reticulum (ER) stress was reflected by the unfolded-protein response and abnormal calcium homeostasis. The ER stress response induces GADD153 and GRP78 protein levels (Liu et al., 2010). Many researches have pointed out that there is a correlation between the increase in GADD153 and the induction of apoptosis in traditional Chinese medicine-treated cancer cells (Chiu et al., 2019, Su et al., 2019). Therefore, this research focused on exploring the cytotoxicity of 50% ethanolic G. paraguayense (N.E.Br.) E. Walther extract (GE50) on human melanoma cells.