Bisphosphonates Induce Breast Cancer Cell Death In Vitro

Fromigué, Olivia; Lagneaux, Laurence; Body, Jean‐Jacques

doi:10.1359/jbmr.2000.15.11.2211

Cited by 247 publications

(166 citation statements)

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“…Bisphosphonates can also decrease the number of bone metastases (Hall and Stoica, 1994;Powles et al, 2002). Moreover, we and others recently demonstrated that, in vitro, bisphosphonates irreversibly reduce breast cancer cell viability by inducing cell death, either by apoptosis or by direct cell necrosis (Fromigue et al, 2000;Senaratne et al, 2000;Jagdev et al, 2001a). The exact mechanism of action of bisphosphonates is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in rats revealed that concentrations as high as 10 À4 M or 10 À3 M can be reached in resorption lacunae (Sato et al, 1991). The concentrations we chose (10 À6 M) could thus be easily reached in the skeleton, and it did not induce strong toxicity in vitro as it can be observed for concentrations of 10 À4 or 10 À3 M (Fromigue et al, 2000). We showed here that this relatively low concentration was able to block growth factors' effects, and to inhibit the 'protective' effect of growth factors on breast cancer cell survival.…”

Section: Discussionmentioning

confidence: 99%

“…After 3, 8, 15, 24 and 48 h of incubation under serum-free conditions, cells were trypsinised and processed as previously described (Fromigue et al, 2000). Briefly, caspases activities were assessed by the cleavage of synthetic fluorogenic substrates containing the amino-acid sequences IETD: Ile-Glu-Thr-Asp (caspase-8), or DEVD: Asp-Glu-Val-Asp (effector caspase -3, -6 and -7) combined to a fluorophore (AMC).…”

Section: Caspase Activitymentioning

confidence: 99%

“…We previously reported that bisphosphonates reduce breast cancer cell survival by inducing both programmed cell death (apoptosis) and direct necrosis in the MCF-7 cell line, whereas necrosis is the main mechanism involved in the reduction of T47D cell survival (Fromigue et al, 2000). The bisphosphonate-induced apoptotic process in MCF-7 cells is characterised by a time-dependent activation of effector caspases.…”

Section: Differential Effects Of Bisphosphonates and Growth Factors Omentioning

confidence: 99%

“…In addition, the inhibitory activity of bisphosphonates on bone resorption may be indirectly mediated by other cells such as cells of the osteoblastic lineage or the macrophage family (Sahni et al, 1993;Nishikawa et al, 1996;Vitte et al, 1996;Siwek et al, 1997;Fromigue and Body, 2002). On the other hand, we and others (Fromigue et al, 2000;Senaratne et al, 2000;Jagdev et al, 2001b) previously showed that bisphosphonates can induce human breast cancer cell death in vitro (apoptosis and/or necrosis), which could contribute to their beneficial clinical effects. Thus, bisphosphonates exhibit beneficial effects on bone integrity by reducing bone resorption induced by osteoclasts and maybe also by direct 'antitumoral' effects.…”

mentioning

confidence: 92%

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Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

2003

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Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone -derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Caspase Activitymentioning

confidence: 99%

Section: Differential Effects Of Bisphosphonates and Growth Factors Omentioning

confidence: 99%

mentioning

confidence: 92%

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Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

2003

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Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer

et al. 2014

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IMPORTANCE Studies have shown that bisphosphonates may have antitumor and antimetastatic properties. Recently, observational studies have suggested a possible protective effect of bisphosphonates on breast cancer, but the effect of bisphosphonate use on risk of breast cancer has not been tested in randomized trials.OBJECTIVE To assess the relationship of postmenopausal breast cancer incidence and bisphosphonate use using data from 2 randomized (1:1), double-blind, placebo-controlled trials. DESIGN, SETTING, AND PARTICIPANTSThe Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55 to 81 years to alendronate or placebo for a mean follow-up of 3.8 years. The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65 to 89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. Data were collected at clinical centers in the United States (FIT and HORIZON-PFT) and in Asia and the Pacific, Europe, North America, and South America (HORIZON-PFT). Women, in either study, with recurrent breast cancer or who reported a history of breast cancer were excluded from analyses. In each trial, a blinded review was conducted of each cancer adverse event report to verify incident invasive breast cancer cases. The primary analysis compared events in the active vs placebo group using a log-rank test. INTERVENTION Alendronate vs placebo (FIT) or zoledronic acid vs placebo (HORIZON-PFT). MAIN OUTCOMES AND MEASURESHazard ratio for incident breast cancer in the bisphosphonate treatment group compared to the placebo group. RESULTSThere was no significant difference in the rate of breast cancer in FIT: 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group (hazard ratio [HR], 1.24 [95% CI, 0.84-1.83]). In HORIZON-PFT, there was also no significant difference: 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group (HR, 1.15 [95% CI, 0.70-1.89]). There was also no significant difference when the data from FIT and HORIZON-PFT were pooled (HR, 1.20 [95% CI, 0.89-1.63]). CONCLUSIONS AND RELEVANCEThese 2 randomized clinical trials do not support the findings from observational research. Contrary to the results from observational studies, we found that 3 to 4 years of bisphosphonate treatment did not decrease the risk of invasive postmenopausal breast cancer.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00049829(HORIZON-PFT)

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A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease

Berenson

Vescio

Henick

et al. 2001

Cancer

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BACKGROUND Bone metastases typically are associated with osteolytic bone destruction, resulting in bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption and represent a significant therapeutic improvement in the management of patients with lytic bone metastases. Zoledronic acid is a new‐generation, highly potent, nitrogen‐containing bisphosphonate that to the authors knowledge is the most potent inhibitor of bone resorption currently in clinical trials. The objectives of the current study were to assess the safety and tolerability of increasing doses of zoledronic acid and to determine its activity with respect to reducing biochemical markers of bone resorption in cancer patients with bone metastases. METHODS Forty‐four cancer patients with bone metastases or primary bone lesions were enrolled sequentially into 1 of 5 fixed ascending‐dose treatment groups. Each patient received a single intravenous bolus injection of 1, 2, 4, 8, or 16 mg of zoledronic acid over 30–60 seconds. Patients were monitored for 8 weeks for the evaluation of clinical findings, adverse events, vital signs, electrocardiograms, markers of bone resorption, and urinary N‐acetyl‐β‐D‐glucosaminidase. RESULTS Zoledronic acid was safe and well tolerated at all dose levels tested. Commonly reported adverse events included bone pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group. Seven patients reported serious adverse events, none of which appeared to be related to the study drug. Zoledronic acid effectively suppressed biochemical markers of bone resorption, including the highly specific markers N‐telopeptide and deoxypyridinoline, for up to 8 weeks in the 2–16‐mg dose groups and for a shorter duration in the 1‐mg group. CONCLUSIONS In the current study, zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption. The authors believe it may improve the treatment of metastatic bone disease. Cancer 2001;91:144–54. © 2001 American Cancer Society.

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Bisphosphonates Induce Breast Cancer Cell Death In Vitro

Cited by 247 publications

References 34 publications

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer

A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease

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