Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines.
BACKGROUND
Bisphosphonates 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.


METHODS
We 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.


RESULTS
Ibandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC50: 10(-4) M for MCF-7 and IBEP-2 cells; 3 x 10(-4) M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17beta-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.


CONCLUSIONS
These 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.
Journe
Fabrice
F
Laboratory of Endocrinology and Bone Diseases and Department of Internal Medicine, Institut J Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Brussels, Belgium. fabrice.journe@bordet.be
Chaboteaux
Carole
C
Magne
Nicolas
N
Duvillier
Hugues
H
Laurent
Guy
G
Body
Jean-Jacques
JJ
D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D000077557:Ibandronic Acid; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000502:physiology; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D000077557:Ibandronic Acid