Farnesyltransferase inhibitor R115777 inhibits cell growth and induces apoptosis in mantle cell lymphoma.
BACKGROUND
The cytotoxic activity of the farnesyltranseferase inhibitor R115777 was evaluated in cell lines representative of mantle cell lymphoma (MCL).


METHODS
Cell growth, proliferation, and apoptosis were analyzed in four human MCL cell lines (Granta, NCEB, REC, and UPN1) in presence of R115777, alone or in combination with vincristin, doxorubicin, bortezomib, cisplatin and cytarabine. Inhibition of farnesylation was determined by the appearance of prelamin A. The antitumor activity of R115777, administered p.o. at 100, 250 and 500 mg/kg, was determined in vivo in nude mice xenografted with UPN1 cells.


RESULTS
R115777 inhibited the growth of MCL cell lines in vitro with inhibitory concentrations ranging between 2 and 15 nM. A fifty percent decrease of cell viability was observed at concentrations comprised between 0.08 and 17 microM. Apoptosis, evaluated by annexin V and activated caspase 3 staining, was induced in all cell lines, in 40 to 71% of the cells depending on the cell lines. In addition, R115777 significantly increased the cytotoxic effect of vincristine, doxorubicin, bortezomib, cisplatin and cytarabine (p=0.001, p=0.016, p=0.006, p=0.014 and p=0.007 respectively). Exposure of MCL cell lines to R115777 during 72 hours resulted in inhibition of protein farnesylation. R115777 administered p.o. twice daily for 8 consecutive days to mice bearing established s.c. UPN1 xenograft displayed cytostatic activity at the 500 mg/kg dosage.


CONCLUSIONS
We have demonstrated that inhibition of farnesyltransferase by R115777 was associated with growth inhibition and apoptosis of MCL cell lines in vitro and tumor xenograft stability in vivo.
Rolland
Delphine
D
Université Joseph Fourier, INSERM U836 (équipe 7), Grenoble, France.
Camara-Clayette
Valérie
V
Barbarat
Aurélie
A
Salles
Gilles
G
Coiffier
Bertrand
B
Ribrag
Vincent
V
Thieblemont
Catherine
C
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D034904:Lamin Type A; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D015363:Quinolones; C090764:prelamin A; D051231:Farnesyltranstransferase; C402769:tipifarnib