Abstract
IntroductionBisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells.MethodsWe examined the anti-proliferative properties of ibandronate on two ER+ breast cancer cell lines (MCF-7 and IBEP-2), and on one ER negative (ER-) cell line (MDA-MB-231). Experiments were performed in steroid-free medium to assess ER regulation and the effect of ibandronate in combination with estrogen or antiestrogens.ResultsIbandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC50: 10-4 M for MCF-7 and IBEP-2 cells; 3 × 10-4 M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17β-estradiol in ER+ breast cancer cells, but affected neither ER regulation nor estrogen-induced progesterone receptor expression, as documented in MCF-7 cells. Moreover, ibandronate enhanced the growth inhibitory action of partial (4-hydroxytamoxifen) and pure (ICI 182,780, now called fluvestrant or Faslodex™) antiestrogens in estrogen-sensitive breast cancer cells. Combination analysis identified additive interactions between ibandronate and ER antagonists.ConclusionThese data constitute the first in vitro evidence for additive effects between ibandronate and antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer.
Highlights
Bisphosphonates are inhibitors of osteoclastmediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer
Effects of ibandronate on breast cancer cell growth in steroid-free medium MCF-7 cells were plated in RPMI 1640 medium supplemented with charcoal-stripped fetal bovine serum (SFM), and cultured for 24 h before exposure for 72 h to ibandronate at
We investigated the effects of ibandronate on the growth of MCF-7, IBEP-2 and MDA-MB-231 cells in medium supplemented with charcoal-stripped serum, providing a steroid-free environment suitable for the assessment of estrogenic responses
Summary
Bisphosphonates are inhibitors of osteoclastmediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells. Bisphosphonates are potent inhibitors of osteoclast-mediated osteolysis [6] and have, emerged as a rational approach for the management of bone metastases [7,8]. These drugs are synthetic analogs of pyrophosphate.
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