New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Denoyelle, Christophe; Li, Hong; Jp, Vannier; Soria, Jeannette; Soria, Claudine

doi:10.1038/sj.bjc.6600925

Cited by 147 publications

(124 citation statements)

References 44 publications

(50 reference statements)

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“…These observations are in agreement with those of Denoyelle and colleagues 33 in breast cancer cells. As in case of the cytotoxic effect, the microfilament activity of ZOL was also blocked by addition of GGOH, but not FOH.…”

Section: Discussionsupporting

confidence: 83%

Anticancer effects of zoledronic acid against human osteosarcoma cells

Kubista

Trieb

Sevelda

et al. 2006

Journal Orthopaedic Research

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Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N ¼ 9). Exposure to ZOL at low micromolar concentrations induced a dose-and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy. ß

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Section: Discussionsupporting

confidence: 83%

Anticancer effects of zoledronic acid against human osteosarcoma cells

Kubista

Trieb

Sevelda

et al. 2006

Journal Orthopaedic Research

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“…The present study demonstrated that FTI-277 effectively inhibited the invasive/migratory phenotypes of H-Ras-MCF10A and Hs578T cells, but not those of MDA-MB-231 cells. Consistent with these results, a previous study observed that FTI-277 did not inhibit the Transwell invasion of MDA-MB-231 cells (36). By contrast, it has been reported that the transendothelial invasion of MDA-MB-231 cells was mildly inhibited by FTI-277 (33).…”

Section: Discussionsupporting

confidence: 80%

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

2016

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Abstract. Hyperactive Ras promotes proliferation and malignant phenotypic conversion of cells in cancer. Ras protein must be associated with cellular membranes for its oncogenic activities through post-translational modifications, including farnesylation. Farnesyltransferase (FTase) is essential for H-Ras membrane targeting, and H-Ras, but not N-Ras, has been demonstrated to cause an invasive phenotype in MCF10A breast epithelial cells. In the present study, it was observed that an FTase inhibitor (FTI), FTI-277, blocked epidermal growth factor (EGF)-induced H-Ras activation, but not N-Ras activation in MDA-MB-231 cells, which express wild-type H-Ras and N-Ras. FTI-277 exerted a more potent inhibitory effect on the proliferation of H-Ras-MCF10A cells and Hs578T breast cancer cells expressing an active mutant of H-Ras than that of MDA-MB-231 cells. The invasive/migratory phenotypes of the H-Ras-MCF10A and Hs578T cells were effectively inhibited by FTI-277 treatment. By contrast, FTI-277 did not affect the invasive/migratory phenotypes of MDA-MB-231 cells. However, the EGF-induced invasion of MDA-MB-231 cells was decreased by FTI-277, implicating that FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation. Taken together, the results of the present study suggest that FTase inhibition by FTI-277 may be an effective strategy for targeting H-Ras-mediated proliferation, migration and invasion of breast cells.

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“…Using an intermediary of this pathway (GGOH), apoptosis was reduced by 50% for cells treated with the sequence ' letrozole then ZA'. Inhibition of the mevalonate pathway by nitrogen-bisphosphonates is integral for inducing a variety of effects including apoptosis of osteoclasts (Amin et al, 1992), breast cancer cells (Jagdev et al, 2001), prostate cancer cells (Oades et al, 2003), myeloma cells (Shipman et al, 1998) and inhibition of tumour cell invasion (Denoyelle et al, 2003). Furthermore, inhibition of this pathway also contributes to the apoptosis induced when breast (and prostate) cancer cells are treated in combination with ZA and doxorubicin (Neville-Webbe et al, 2005), or when breast cancer cells are treated with ZA and paclitaxel (Neville-Webbe et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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

2010

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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.

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New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

Cited by 147 publications

References 44 publications

Anticancer effects of zoledronic acid against human osteosarcoma cells

Anticancer effects of zoledronic acid against human osteosarcoma cells

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

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

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