Abstract
Melanoma is the leading cause of skin cancer deaths, and the poor prognosis of metastatic melanoma has made needs for a novel pharmacological treatment or efficient intervention. Carnosol, a major polyphenolic compound from Rosmarinus officinalis, has a wide range of biological activities including anti-cancer effect. However, the underlying molecular mechanisms of its anti-cancer effect remain poorly understood in malignant human melanoma cells. In the present study, we investigate the apoptotic effect and the underlying anti-cancer mechanisms of carnosol. Our results revealed that carnosol strongly induced apoptosis against human melanoma G361 cells in a dose- and time-dependent manner, and caused dramatical elevation in cellular reactive oxygen species (ROS) level during apoptosis. In mechanistic studies, carnosol treatment decreased protein level of anti-apoptotic B‑cell lymphoma 2 (Bcl-2) and B cell lymphoma-extra large (Bcl-xL), however, increased level of pro-apoptotic Bcl-2-associated X protein (Bax) protein. Moreover, carnosol escalated cellular level of p53, which was accompanied by a decline of mouse double minute 2 homolog (MDM2) level. Also, carnosol inhibited activation of Src and signal transducer and activator of transcription 3 (STAT3), therefore down-regulated STAT3-dependent gene expression, such as D-series cyclin and survivin. These changes by carnosol were attenuated by pre-treatment of N-acetyl cysteine, and abolished progression of carnosol-induced apoptosis. In conclusion, carnosol induced apoptosis in human melanoma G361 cells through ROS generation and inhibition of STAT3-mediated pathway. Our results provide molecular bases of carnosol-induced apoptosis, and suggest a novel candidate for human melanoma treatment.
Highlights
Melanoma, a malignant tumor derived from melanocytes, causes the majority of deaths attributed to skin cancer
Effect of carnosol on cell viability in human melanoma G361 cells To examine the effect of carnosol on the viability of human melanoma G361 cells, we performed MTT assay after treatment of carnosol
At 100 μM of carnosol-treated group, the cells were revealed approximately 80% of the apoptotic cell population as compared to untreated cells after 24 h of treatment (Fig. 1d, e). These results showed that the treatment of carnosol to G361 cells dramatically increased apoptotic cell death as compared with untreated control cells
Summary
A malignant tumor derived from melanocytes, causes the majority of deaths attributed to skin cancer. The incidence of melanoma, the most fatal form of skin cancer, has increased significantly over the past 20 years [1]. Melanoma has been treated by various ways. Surgical excision is a representative treatment in early stages of the disease [2], in addition, RAF and MEK kinase-targeted chemotherapy or immunotherapy using. Known as programmed cell death, is triggered by extrinsic and intrinsic ligands. These two different apoptotic pathways are regulated by diverse intracellular signaling pathways and coordinated by a network of genes [7]. Activation of caspase cascade leads to the cleavage of
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