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

Author(s):Show less -

Brohem, Carla A. ^[1] ; Massaro, Renato R. ^[1] ; Tiago, Manoela ^[1] ; Marinho, Camila E. ^[1] ; Jasiulionis, Miriam G. ^[2] ; de Almeida, Rebeca L. ^[1] ; Rivelli, Diogo P. ^[1] ; Albuquerque, Renata C. ^[1] ; de Oliveira, Tiago F. ^[1] ; de Melo Loureiro, Ana P. ^[1] ; Okada, Sabrina ^[1] ; Soengas, Maria S. ^[3] ; de Moraes Barros, Silvia B. ^[1] ; Maria-Engler, Silvya S. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[3] Spanish Natl Canc Res Ctr, Ctr Nacl Invest Oncol, Madrid - Spain

• Document type: Journal article
• Source: PIGMENT CELL & MELANOMA RESEARCH; v. 25, n. 3, p. 354-369, MAY 2012.
• Web of Science Citations: 27

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. (AU)

• FAPESP's process: 08/58817-4 - Generation of human artificial skins and invasive melanomas as a platform for pharmacological testing
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Regular Research Grants
• FAPESP's process: 06/50479-7 - Action of Pothomorphe umbellata extract on the extracellular matrix components in the skin healing process: in vivo and in vitro models
• Grantee: Carla Abdo Brohem
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 09/54816-6 - Xenobiotic effects in cultured human cells and study of mechanisms of cytotoxic and genotoxic damage
• Grantee: Ana Paula de Melo Loureiro
• Support Opportunities: Regular Research Grants