Abstract
Chaetocin is a small-molecule natural product produced by Chaetomium species fungi, and it has a potent anti-proliferative pharmacological activity on various cancer cells. However, the effect of chaetocin on anti-melanoma pharmacological role has not been investigated. Therefore, in this study, we explored the effect of chaetocin on cell proliferation in the human melanoma Sk-Mel-28 and A375 cells and the growth of tumor xenografts in nude mice. The results indicated that chaetocin treatment significantly suppressed cell proliferation and induced apoptosis in the Sk-Mel-28 and A375 cells in a dose- and time-dependent manner. Furthermore, chaetocin treatment resulted in an increased level of cellular reactive oxygen species (ROS), and pre-incubation of cells with N-acetylcysteine (NAC) significantly abrogated chaetocin-induced apoptosis in the melanoma cells. A significant reduction of mitochondrial membrane potential and the release of cytochrome c were observed after chaetocin treatment. Additionally, chaetocin treatment significantly up-regulated the protein levels of Bax, cleaved caspase-9/-3, simultaneously down-regulated the protein levels of Bcl-2, procaspase-9/-3, and activated caspase-9/-3 activity in the melanoma cells. The in vivo data demonstrated that chaetocin treatment significantly inhibited the growth of melanoma tumor xenografts in nude mice, which was closely associated with apoptosis induction, a reduced level of PCNA (proliferating cell nuclear antigen) expression, and activation of capase-9/-3 in tumor xenografts. These are the first data to demonstrate that chaetocin exerts a proapoptotic activity on human melanoma cells through ROS generation and the intrinsic mitochondrial pathway. Therefore, chaetocin might represent an effective candidate for melanoma chemotherapy.
Highlights
Melanoma is one of the most aggressive forms of skin cancers with a high frequency of metastasis and with very poor prognosis in the metastatic stage [1]
The results indicated that chaetocin (5 and 10 μM) treatment on the Sk-Mel-28 and A375 cells for 24 h resulted in a significant increase of apoptotic cells (Annexin V-FITC+/PI− and Annexin V-FITC+/PI+ cells), and demonstrated an apoptosisinduced effect in a concentration-dependent manner (Fig 2A and 2B)
10 μM chaetocin treatment on these cells for 24, 48 and 72 h produced a gradual increase of apoptotic cells (Fig 2C and 2D), which displayed that chaetocin could induce apoptosis in Sk-Mel-28 and A375 cells in a time-dependent manner
Summary
Melanoma is one of the most aggressive forms of skin cancers with a high frequency of metastasis and with very poor prognosis in the metastatic stage [1]. Melanoma represents 4% of dermatologic cancers, it is responsible for 80% of skin cancer deaths because of its aggression, metastasis and drug-resistance [2]. If patients were early diagnosed with primary melanoma, surgical resection is the best choice for most of them to reduce mortality [3]. A 5-year survival rate in metastatic melanoma is still under 15–20% of patients [4]. Novel therapeutic strategies that inhibit melanoma growth and progression need to be developed for improving the survival of patients with melanomas [5]
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