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Proteasome inhibition and ROS generation by 4‐nerolidylcatechol induces melanoma cell death

2012; Wiley; Volume: 25; Issue: 3 Linguagem: Inglês

10.1111/j.1755-148x.2012.00992.x

1755-148X

Carla Abdo Brohem, Renato Ramos Massaro, Manoela Tiago, Camila E. Marinho, Miriam Galvonas Jasiulionis, Rebeca Leite de Almeida, Diogo Pineda Rivelli, Renata Chaves Albuquerque, Tiago Franco de Oliveira, Ana Paula de Melo Loureiro, Sabrina Sayori Okada, Marı́a S. Soengas, Sílvia Berlanga de Moraes Barros, Silvya Stuchi Maria‐Engler,

Cell death mechanisms and regulation

Summary 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.