Characterization of a R115777-resistant human multiple myeloma cell line with cross-resistance to PS-341.
The farnesyl transferase inhibitor R115777 has been found to have clinical activity in diverse hematopoietic tumors. Clinical efficacy, however, does not correlate with Ras mutation status or inhibition of farnesyl transferase. To further elucidate the mechanisms by which R115777 induces apoptosis and to investigate drug resistance, we have identified and characterized a R115777-resistant human myeloma cell line. 8226/R5 cells were found to be at least 50 times more resistant to R115777 compared with the parent cell line 8226/S. K-Ras remained prenylated in both resistant and sensitive cells after R115777 treatment; however, HDJ-2 farnesylation was inhibited in both lines, implying that farnesyl transferase (the drug target) has not been mutated. Whereas many 8226 lines that acquire drug resistance have elevated expression of P-glycoprotein, we found that P-glycoprotein expression is not increased in the 8226/R5 line and intracellular accumulation of R115777 was not reduced. In fact, 8226/R5 cells were insensitive to a diverse group of antitumor agents including PS-341, and multidrug resistance did not correlate with the expression of heat shock proteins. Comparison of gene expression profiles between resistant and sensitive cells revealed expression changes in several genes involved in myeloma survival and drug resistance. Future experiments will attempt to identify genes that are directly linked to the resistant phenotype. Identification of molecules associated with R115777 and PS-341 resistance is clinically relevant because both compounds are being tested in solid tumors and hematopoietic malignancies.
Buzzeo
Robert
R
Department of Interdisciplinary Oncology, Malignant Hematology and Experimental Therapeutics Division, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612-9497, USA.
Enkemann
Steven
S
Nimmanapalli
Rama
R
Alsina
Melissa
M
Lichtenheld
Mathias G
MG
Dalton
William S
WS
Beaupre
Darrin M
DM
D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D008558:Melphalan / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D019311:Staurosporine / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
D001897:Boronic Acids; D006360:Heat-Shock Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D015363:Quinolones; D014415:Tunicamycin; D000069286:Bortezomib; D005047:Etoposide; D004317:Doxorubicin; D051231:Farnesyltranstransferase; D018631:ras Proteins; D019311:Staurosporine; C402769:tipifarnib; D008558:Melphalan