Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines.
BACKGROUND
Cutaneous malignant melanoma is an aggressive type of skin cancer which causes disproportionate mortality in young and middle-aged adults. Once disseminated, melanoma can be considered an incurable disease, highly resistant to standard antineoplastic treatment, such as chemotherapy or radiation therapy. The proteasome represents a novel target for cancer therapy that can potentially be used in melanoma.


OBJECTIVE
To assess the effect of four structurally different proteasome inhibitors on human cutaneous melanoma-derived cell lines.


METHODS
Sixteen human cutaneous melanoma-derived cell lines which are original were obtained from patients who were treated by two of the authors. Cells were cultured, exposed to proteasome inhibitors (bortezomib, ALLN, MG-132 and epoxomicin) and then assayed for cell cycle and cell death analyses.


RESULTS
Proteasome inhibitors inhibited the in vitro growth of melanoma cells, and this effect was due to a reduction in cell proliferation rate and an induction of both caspase-dependent and caspase-independent cell death. Moreover, release of apoptosis-inducing factor was observed in the presence of the broad-specificity caspase inhibitor BAF (Boc-D-fmk). In addition, the four different proteasome inhibitors induced caspase 2 processing.


CONCLUSIONS
This study provides information regarding the in vitro effects of proteasome inhibitors on melanoma cell lines, and the molecular mechanisms involved. It also gives support to the future use of such inhibitors in the treatment of patients with melanoma, either administered alone or in combination with other drugs.
Sorolla
A
A
Department of Dermatology, and Laboratory of Research, Hospital Universitair Arnau de Vilanova, Universitat de Lleida, 25198 Lleida, Spain.
Yeramian
A
A
Dolcet
X
X
Pérez de Santos
A M
AM
Llobet
D
D
Schoenenberger
J A
JA
Casanova
J M
JM
Soria
X
X
Egido
R
R
Llombart
A
A
Vilella
R
R
Matias-Guiu
X
X
Marti
R M
RM
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000209:etiology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000209:etiology; D016896:Treatment Outcome
D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib