CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth.
OBJECTIVE
Renal cell carcinoma often presents asymptomatically and patients are commonly diagnosed at the metastatic stage, when treatment options are limited and survival is poor. Since progression-free survival using current therapy for metastatic renal cell carcinoma is only 1 to 2 years and existing drugs are associated with a high resistance rate, new pharmacological targets are needed. We identified and evaluated the nuclear exporter protein CRM1 as a novel potential therapy for renal cell carcinoma.


METHODS
We tested the efficacy of the CRM1 inhibitors KPT-185 and 251 in several renal cell carcinoma cell lines and in a renal cell carcinoma xenograft model. Apoptosis and cell cycle arrest were quantified and localization of p53 family proteins was assessed using standard techniques.


RESULTS
KPT-185 attenuated CRM1 and showed increased cytotoxicity in renal cell carcinoma cells in vitro with evidence of increased apoptosis as well as cell cycle arrest. KPT-185 caused p53 and p21 to remain primarily in the nucleus in all renal cell carcinoma cell lines, suggesting that the mechanism of action of these compounds depends on tumor suppressor protein localization. Furthermore, when administered orally in a high grade renal cell carcinoma xenograft model, the bioavailable CRM1 inhibitor KPT-251 significantly inhibited tumor growth in vivo with the expected on target effects and no obvious toxicity.


CONCLUSIONS
The CRM1 inhibitor protein family is a novel therapeutic target for renal cell carcinoma that deserves further intensive investigation for this and other urological malignancies.
Division of Nephrology, Department of Internal Medicine, University of California-Davis, Davis, California 95616, USA.
Hiromi
H
Inoue
Michael
M
Kauffman
Sharon
S
Shacham
Yosef
Y
Landesman
Joy
J
Yang
Christopher P
CP
Evans
Robert H
RH
Weiss
D000179:Acrylates / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D045744:Cell Line, Tumor / Q000187:drug effects; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D028884:Karyopherins / Q000187:drug effects* / Q000235:genetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D009368:Neoplasm Transplantation; D011897:Random Allocation; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics; D012680:Sensitivity and Specificity; D015996:Survival Rate; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D000097606:Exportin 1 Protein
D000179:Acrylates; D000970:Antineoplastic Agents; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185