Proteasome inhibition and ROS generation by 4-nerolidylcatechol induces melanoma cell death |
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Authors: | Brohem Carla A Massaro Renato R Tiago Manoela Marinho Camila E Jasiulionis Miriam G de Almeida Rebeca L Rivelli Diogo P Albuquerque Renata C de Oliveira Tiago F de Melo Loureiro Ana P Okada Sabrina Soengas María S de Moraes Barros Silvia B Maria-Engler Silvya S |
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Institution: | 1. Department of Clinical Chemistry & Toxicology, School of Pharmaceutical Sciences, University of S?o Paulo, S?o Paulo, Brazil;2. Pharmacology Department, Federal University of S?o Paulo, S?o Paulo, Brazil;3. Centro Nacional de Investigaciones Oncológicas (Spanish National Cancer Research Center) Madrid, Spain |
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Abstract: | Induction of apoptotic cell death in response to chemotherapy and other external stimuli has proved extremely difficult in melanoma, leading to tumor progression, metastasis formation and resistance to therapy. A promising approach for cancer chemotherapy is the inhibition of proteasomal activity, as the half‐life of the majority of cellular proteins is under proteasomal control and inhibitors have been shown to induce cell death programs in a wide variety of tumor cell types. 4‐Nerolidylcatechol (4‐NC) is a potent antioxidant whose cytotoxic potential has already been demonstrated in melanoma tumor cell lines. Furthermore, 4‐NC was able to induce the accumulation of ubiquitinated proteins, including classic targets of this process such as Mcl‐1. As shown for other proteasomal inhibitors in melanoma, the cytotoxic action of 4‐NC is time‐dependent upon the pro‐apoptotic protein Noxa, which is able to bind and neutralize Mcl‐1. We demonstrate the role of 4‐NC as a potent inducer of ROS and p53. The use of an artificial skin model containing melanoma also provided evidence that 4‐NC prevented melanoma proliferation in a 3D model that more closely resembles normal human skin. |
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Keywords: | 4‐nerolidylcatechol melanoma apoptosis Noxa proteasomal inhibitor artificial skin |
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