title: Proteasome inhibition and ROS generation by 4-nerolidylcatechol induces melanoma cell death.
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.
authors.affiliation: Department of Clinical Chemistry & Toxicology, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Brohem
authors.forename: Renato R
authors.initials: RR
authors.lastname: Massaro
authors.forename: Manoela
authors.initials: M
authors.lastname: Tiago
authors.forename: Camila E
authors.initials: CE
authors.lastname: Marinho
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Jasiulionis
authors.forename: Rebeca L
authors.initials: RL
authors.lastname: de Almeida
authors.forename: Diogo P
authors.initials: DP
authors.lastname: Rivelli
authors.forename: Renata C
authors.initials: RC
authors.lastname: Albuquerque
authors.forename: Tiago F
authors.initials: TF
authors.lastname: de Oliveira
authors.forename: Ana P
authors.initials: AP
authors.lastname: de Melo Loureiro
authors.forename: Sabrina
authors.initials: S
authors.lastname: Okada
authors.forename: María S
authors.initials: MS
authors.lastname: Soengas
authors.forename: Silvia B
authors.initials: SB
authors.lastname: de Moraes Barros
authors.forename: Silvya S
authors.initials: SS
authors.lastname: Maria-Engler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002396:Catechols / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D008954:Models, Biological; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012878:Skin Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: C110583:4-nerolidylcatechol; D000970:Antineoplastic Agents; D000975:Antioxidants; D002396:Catechols; D004273:DNA, Neoplasm; D016166:Free Radical Scavengers; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species