Pamidronate resistance and associated low ras levels in breast cancer cells: A role for combinatorial therapy

Ping L. Zhang, Mingyue Lun, Nava Siegelmann-Danieli, Thomas M. Blasick, Robert E. Brown*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)263-270
Number of pages8
JournalAnnals of Clinical and Laboratory Science
Volume34
Issue number3
StatePublished - Jun 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Breast cancer
  • Gleevec
  • H-ras
  • N-ras
  • Pamidronate
  • Velcade

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