Combining the endoplasmic reticulum stress-inducing agents bortezomib and fenretinide as a novel therapeutic strategy for metastatic melanoma.
OBJECTIVE
Single-agent chemotherapy is largely the treatment of choice for systemic therapy of metastatic melanoma, but survival rates are low, and novel adjuvant and systemic therapies are urgently required. Endoplasmic reticulum (ER) stress is a potential therapeutic target, and two relatively new drugs, fenretinide and bortezomib (Velcade), each acting via different cellular mechanisms, induce ER stress leading to apoptosis in melanoma cells. The aim of this study was to test the hypothesis that apoptosis of melanoma cells may be increased by combining clinically achievable concentrations of fenretinide and bortezomib.


METHODS
Three human melanoma cell lines were used to assess changes in viability and the induction of apoptosis in response to fenretinide, bortezomib, or both drugs together. A s.c. xenograft model was used to test responses in vivo.


RESULTS
Fenretinide and bortezomib synergistically decreased viability and increased apoptosis in all three melanoma lines at clinically achievable concentrations. This was also reflected by increased expression of GADD153, a marker of ER stress-induced apoptosis. In vivo, fenretinide in combination with bortezomib gave a marked reduction in xenograft tumor volume and an increase in apoptosis compared with fenretinide or bortezomib alone. The cell cycle stage of tumor cells in vivo were similar to that predicted from the effects of each drug or the combination in vitro.


CONCLUSIONS
These results suggest that fenretinide and bortezomib, both of which are available in clinical formulation, warrant clinical evaluation as a combination therapy for metastatic melanoma.
Hill
David S
DS
Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, United Kingdom.
Martin
Shaun
S
Armstrong
Jane L
JL
Flockhart
Ross
R
Tonison
Joge J
JJ
Simpson
Dominic G
DG
Birch-Machin
Mark A
MA
Redfern
Christopher P F
CP
Lovat
Penny E
PE
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D051379:Mice; D011719:Pyrazines / Q000008:administration & dosage*
D001897:Boronic Acids; D019394:Ki-67 Antigen; D011719:Pyrazines; D017313:Fenretinide; D000069286:Bortezomib