Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implication for bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma.
Melanoma poses a great challenge to patients, oncologists, and biologists because of its nearly universal resistance to chemotherapy. Many studies have shown that nuclear factor kappaB is constitutively activated in melanoma, thereby promoting the proliferation of melanoma cells by inhibiting the apoptotic responses to chemotherapy. Nuclear factor kappaB activity is regulated by phosphorylation and subsequent degradation of inhibitor of nuclear factor kappaB by the ubiquitin-proteasome pathway. In this study, we show that the novel proteasome inhibitor, bortezomib, inhibited the growth of melanoma cells in vitro at a concentration range of 0.1-10 nM and in combination with the chemotherapeutic agent temozolomide, the inhibitory effect on melanoma cell growth was even more prominent. Data from a murine model showed reduced tumor growth when bortezomib was administered to human melanoma tumors. Strikingly, animals receiving bortezomib in combination with temozolomide achieved complete remission of palpable tumors after only 30 days of therapy, lasting >200 days. Our data indicate strongly that bortezomib in combination with chemotherapeutic agents should be studied additionally for the treatment of melanoma.
Amiri
Katayoun I
KI
Department of Veterans Affairs, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Horton
Linda W
LW
LaFleur
Bonnie J
BJ
Sosman
Jeffrey A
JA
Richmond
Ann
A
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D000077204:Temozolomide
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003606:Dacarbazine; D000077204:Temozolomide