RESUMO
ABSTRACT: Merkel cell carcinoma (MCC) is known as a rare and highly malignant neuroendocrine skin cancer and often occurs in the sun-exposed parts of the elderly individuals. In this article, we reported 2 cases of MCC and reviewed relative literature. Case 1 was a 91-year-old woman who presented with a half-year history of a brown nodule on the left temple. The histopathological and immunohistochemistry examination diagnosis was MCC with negative staining of Merkel cell polyomavirus large T antigen (CM2B4). Case 2 was a 76-year-old man with a nodule on his right buttock that gradually increased from approximately 3 mm to 1.5 cm in diameter in 1 month without pain. The biopsy diagnosis was MCC with positive staining of CM2B4. Previous studies have found that the genetic mutation and prognosis of polyomavirus-associated MCC (MCCP) and nonviral MCC (MCCN) are significantly different. Large T antigen plays a crucial role in Merkel cell polyomavirus (MCPyV) oncogenesis. Testing for the MCPyV at the onset of MCC is recommended, which is helpful in predicting the prognosis of patients.
RESUMO
BRAF inhibitors are some of the most effective drugs against melanoma; however, their clinical application is largely limited by drug resistance. Juglone, isolated from walnut trees, has demonstrated antitumour activity. In the present study, it was investigated whether juglone could enhance the responses to a BRAF inhibitor in melanoma cells (A375R and SKMEL5R) with an acquired resistance. These cells were treated with juglone alone, BRAF inhibitor (PLX4032) alone, or juglone combined with PLX4032. It was demonstrated that the combination of juglone and PLX4032 had synergistic effects on BRAF inhibitorresistant melanoma cells. Juglone potentiated PLX4032induced cytotoxicity and mitochondrial apoptosis in both A375R and SKMEL5R cells, which was accompanied by a decline in mitochondrial membrane potential and a decrease in Bcl2/Bax ratio. Moreover, juglone combined with PLX4032 markedly increased the intracellular level of reactive oxygen species (ROS) and activated p38 and p53, as compared with juglone alone or PLX4032 alone. Pretreatment with NacetylLcysteine, a ROS scavenger, completely reversed the cytotoxicity induced by juglone combined with PLX4032. In conclusion, juglone potentiated BRAF inhibitorinduced apoptosis in resistant melanoma cells, and these effects occurred partially through ROS and the p38p53 pathway, suggesting the potential of juglone as a sensitizer to BRAF inhibitors in the treatment of melanoma.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Melanoma/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vemurafenib/farmacologia , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/metabolismo , Melanoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismoRESUMO
Metastatic melanoma is the most aggressive skin cancer. Although BRAF inhibitor treatment has achieved great success in melanoma, resistance develops within 12 months. Icariside II (IS), a natural compound extracted from Herba Epimedii, exerts anticancer properties. In the present study, we determined by MTT, flow cytometry and western blotting, respectively that IS potentiated the PLX4032induced downregulation of cell viability and increase in apoptosis and autophagy in BRAF inhibitorresistant melanoma. In addition, we also revealed by flow cytometry and western blotting, respectively, that IS combined with PLX4032 increased mitochondrial and intracellular reactive oxygen species (ROS) generation and subsequently promoted depolarization of mitochondria and release of apoptotic proteins. Nacetyl cysteine (NAC) and glutathione (GSH), ROS scavengers, reversed the ISinduced enhancement of the response to PLX4032. Microphthalmiaassociated transcription factor (MITF) and tyrosineprotein kinase Met (cMet) are wellknown factors that contribute to BRAF inhibitor resistance. Furthermore, cMet is a direct transcriptional target of MITF in melanocytes and melanoma cells. It was also revealed that IS markedly inhibited MITF and cMet expression partially by increasing ROS production in BRAF inhibitorresistant melanoma cells.