Pamidronate resistance and associated low ras levels in breast cancer cells: a role for combinatorial therapy.
To identify markers sensitive to inhibitors of the farnesylation pathway, we used 3 breast cancer cell lines (SKBR-3, MDA-175, and MDA-231) to evaluate the in vitro effects of pamidronate, an inhibitor of farnesyl diphosphate synthase. In response to pamidronate, there was significant inhibition of cell proliferation in MDA-231 and SKBR-3 cells, compared to MDA-175 cells. This correlated with their respective basal levels of N-ras and H-ras. N-ras and H-ras protein levels were both reduced in MDA-231 cells, and to lesser extent in SKBR-3 cells, following exposure to pamidronate, whereas these markers were not altered in MDA-175 cells. Combinatorial therapy with pamidronate and Gleevec, an inhibitor of several tyrosine kinases; Velcade, a proteasome inhibitor; or rapamycin, an inhibitor of the mammalian target of rapamycin (m-TOR) all showed additive effects in causing proliferative inhibition in MDA-175 cells. In summary, resistance to pamidronate may result from low levels of GTPase-activating proteins, such as N-ras and H-ras, in tumor cells. Combinatorial therapies directed against other signaling pathways, not dependent upon ras, may be required to overcome such resistance.
Zhang
Ping L
PL
Department of Laboratory Medicine, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
Lun
Mingyue
M
Siegelmann-Danieli
Nava
N
Blasick
Thomas M
TM
Brown
Robert E
RE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000627:therapeutic use*; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D000077268:Pamidronate; D010879:Piperazines / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D018631:ras Proteins / Q000378:metabolism*
D001549:Benzamides; D001897:Boronic Acids; D004164:Diphosphonates; D004338:Drug Combinations; D010879:Piperazines; D011719:Pyrazines; D011743:Pyrimidines; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D018631:ras Proteins; D000077268:Pamidronate; D020123:Sirolimus