Combined effects of the bisphosphonate, zoledronic acid and the aromatase inhibitor letrozole on breast cancer cells in vitro: evidence of synergistic interaction

Abstract

BACKGROUND: Aromatase inhibitors are widely used in the treatment of oestrogen receptor-positive post-menopausal breast cancer. These patients may also be receiving the bisphosphonate, zoledronic acid (ZA) to prevent bone loss or reduce skeletal morbidity in the setting of advanced disease. The potential biological interaction of these two drugs in breast cancer has not been assessed. METHODS: Aromatase-expressing breast cancer cells were treated with letrozole and ZA either simultaneously or in sequence, and the resulting apoptosis was assessed by staining with Hoechst 33342 and propidium iodide and examined using a fluorescent inverted Leica DMIRB microscope and a UV filter. RESULTS: We found that letrozole and ZA induce levels of apoptosis in breast cancer cells in vitro that are significantly greater compared with treatment with each drug alone. However, this potentially, synergistic relationship is drug-sequence dependent, occurring only when cells are treated with letrozole, followed by ZA. The converse sequence, or administering drugs simultaneously, induces levels of apoptosis no greater than each drug alone. CONCLUSION: Owing to the enhanced anti-tumour efficacy of sequential drug administration, our findings may indicate that, for post-menopausal women who require treatment with letrozole, ZA should also be considered.

Zoledronic acid inhibits aromatase activity and phosphorylation: Potential mechanism for additive zoledronic acid and letrozole drug interaction

“…This differs dramatically from the study published by Neville-Webbe and colleagues in 2010 [15], who report a synergistic drug effect following concurrent letrozole and zoledronic acid treatment and no effect following simultaneous treatment with both compounds. There are differences between the two study designs which may account for these conflicting results.…”

“…Neville-Webbe and colleagues [15] published data which shows that the combination of letrozole at 100nM and zoledronic acid at 10μM results in a synergistic effect on decreasing cell viability when used in MCF-7Ca (MCF-7 cells, which are human estrogen receptor positive breast cancer cells and transfected with human aromatase construct) breast cancer cells with concurrent treatment of 24h letrozole followed by 24h zoledronic acid. Although the results of this study provided insight into the pharmacological nature of this combination, no mechanism was proposed to explain the effects on cell viability.…”

Adjuvant bisphosphonates

“…Preclinical studies have suggested that bisphosphonates may exert direct anticancer and antimetastatic effects, alone or in combination with chemotherapy and endocrine therapy [8,31]. The bone marrow might also provide an inadvertent sanctuary for disseminated tumor cells (DTCs), which may exploit hematopoietic stem cell niches in the bone marrow to escape the effects of systemic anticancer therapies and seed subsequent relapses [32].…”

Endocrine Therapy in the Preoperative Setting and Strategies to Overcome Resistance

“…Preclinical and clinical data suggest that zolendronic acid, a nitrogen-containing bisphosphonate, is synergistic with AIs in inducing apoptosis [42]. Zolendronic acid has been shown to improve disease-free survival (DFS) of premenopausal women with breast cancer in the adjuvant setting when added to endocrine therapy (HR 0.64; P=0.01) [43].…”