Abstract
Malignant melanoma is the most life-threatening neoplasm of the skin. Despite the increase in incidence, melanoma is becoming more resistant to current therapeutic agents. The bioactive compound frugoside has been recently reported to inhibit growth when used in various cancer cells. However, this effect has not been demonstrated in melanoma. Here, we found that frugoside inhibited the rate of reduction of hyperoxidized peroxiredoxins (Prxs) by downregulating sulfiredoxin (Srx) expression. Furthermore, frugoside increased the accumulation of sulfinic Prxs and reactive oxygen species (ROS) and stimulated p-p38 activation, resulting in the mitochondria-mediated death of M14 and A375 human melanoma cells. The mitochondria-mediated cell death induced by frugoside was inhibited by the overexpression of Srx and antioxidants, such as N-acetyl cysteine and diphenyleneiodonium. In addition, we observed that frugoside inhibited tumor growth without toxicity through a M14 xenograft animal model. Taken together, our findings reveal that frugoside exhibits a novel antitumor effect based on a ROS-mediated cell death in melanoma cells, which may have therapeutic implications.
Highlights
Melanoma, a type of skin cancer, exhibits traits that include high metastatic potential, resistance to chemotherapy, and a poor survival rate [1,2,3]
We reported that frugoside induces oxidative mitochondrial damage and mitochondria-mediated apoptotic cell death by inhibiting Srx expression and delaying the reduction of hyperoxidized Prx in melanoma cells
To further confirm whether decreased Srx expression affects hyperoxidized Prxs, we examined the reduction of sulfinic Prxs in melanoma cells cultured in the presence of frugoside
Summary
A type of skin cancer, exhibits traits that include high metastatic potential, resistance to chemotherapy, and a poor survival rate [1,2,3]. The incidence of melanoma increases at a faster rate than any other cancer worldwide [4,5]. We require novel therapeutics with a higher efficiency and fewer side effects; natural compounds might play a crucial role in the development of new anti-cancer agents [11,12,13]. Natural compounds have long been known as sources of drugs against several human diseases, including cancer. Despite the discovery of natural cytotoxic agents, the search for new anti-cancer drugs remains necessary in order to meet the demand for fewer severe side effects and higher efficiency in therapies
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