Apomine™, an inhibitor of HMG‐CoA‐reductase, promotes apoptosis of myeloma cells <i>in vitro</i> and is associated with a modulation of myeloma <i>in vivo</i>

Edwards, Claire; Mueller, Gabrielle; Roelofs, Anke J.; Chantry, Andrew D.; Perry, Mark; Russell, R. G. G.; Camp, Ben Van; Guyon-Gellin, Yves; Niesor, Eric J.; Bentzen, C.; Vanderkerken, Karin; Croucher, Peter I.

doi:10.1002/ijc.22478

Cited by 21 publications

(14 citation statements)

References 30 publications

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“…It has been clearly shown that several different bisphosphonates can reduce tumor-induced osteolytic bone disease in animal models of a variety of cancers that metastasize to bone, including breast (8,10,32,33), bladder (34,35), and prostate cancer (16, 36 -38) as well as multiple myeloma (11,39,40).…”

Section: Discussionmentioning

confidence: 99%

Differential Effect of Doxorubicin and Zoledronic Acid on Intraosseous versus Extraosseous Breast Tumor Growth In vivo

Ottewell¹,

Deux

Mönkkönen

et al. 2008

Clinical Cancer Research

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Purpose: Breast cancer patients with bone metastases are commonly treated with chemotherapeutic agents such as doxorubicin and zoledronic acid to control their bone disease. Sequential administration of doxorubicin followed by zoledronic acid has been shown to increase tumor cell apoptosis in vitro.We have therefore investigated the antitumor effects of clinically relevant doses of these drugs in a mouse model of breast cancer bone metastasis. Experimental Design: MDA-MB-231/BO2 cells were injected via the tail vein into athymic mice. Tumor-induced osteolytic lesions were detected in all animals following X-ray analysis 18 days after tumor cell inoculation (day 18). Mice were administered saline, 100 Ag/kg zoledronic acid, 2 mg/kg doxorubicin, doxorubicin and zoledronic acid simultaneously, or doxorubicin followed 24 h later by zoledronic acid. Doxorubicin-treated animals received a second injection on day 25. Tumor growth in the marrow cavity and on the outside surface of the bone was measured as well as tumor cell apoptosis and proliferation.The effects of treatments on bone were evaluated following X-ray and ACTanalysis. Results: Sequential treatment with doxorubicin followed by zoledronic acid caused decreased intraosseous tumor burden, which was accompanied by increased levels of tumor cell apoptosis and decreased levels of proliferation, whereas extraosseous parts of the same tumors were unaffected. Administration of zoledronic acid, alone or in combination with doxorubicin, resulted in significantly smaller tumor-induced osteolytic lesions compared with control or doxorubicintreated animals. Conclusions: This is the first study to show that sequential treatment with clinically relevant doses of doxorubicin, followed 24 h later by zoledronic acid, reduces intraosseous but not extraosseous growth of BO2 breast tumors. Our results suggest that breast cancer patients with metastatic bone disease may benefit from sequential treatment using doxorubicin and zoledronic acid.

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Section: Discussionmentioning

confidence: 99%

Differential Effect of Doxorubicin and Zoledronic Acid on Intraosseous versus Extraosseous Breast Tumor Growth In vivo

Ottewell¹,

Deux

Mönkkönen

et al. 2008

Clinical Cancer Research

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“…The Radl model uses 5T myeloma cells that arose spontaneously in aged, inbred C57BL/KaLwRijHsd mice and is propagated by the inoculation of these myeloma cells into syngeneic mice (Radl et al, 1979;Radl et al, 1988;Garrett et al, 1997). Both of these models allow the study of tumor growth and myeloma bone disease, and have proven to be effective preclinical models to test novel therapeutic approaches for the treatment of myeloma bone disease (Dallas et al, 1999;Croucher et al, 2001;Croucher et al, 2003;Oyajobi et al, 2003;Yaccoby et al, 2004;Edwards et al, 2007;Yaccoby et al, 2007;Edwards et al, 2008). Activation of Myc under the control of the kappa light chain regulatory elements results in the development of myeloma with features that are similar to human multiple myeloma (Chesi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

A murine model of myeloma that allows genetic manipulation of the host microenvironment

Fowler¹,

Mundy

Lwin

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARY Multiple myeloma, and the associated osteolytic bone disease, is highly dependent upon cellular interactions within the bone marrow microenvironment. A major limitation of existing myeloma models is the requirement for a specific host strain of mouse, preventing molecular examination of the bone marrow microenvironment. The aim of the current study was to develop a model of myeloma in which the host microenvironment could be modified genetically. The Radl 5T murine model of myeloma is well characterized and closely mimics human myeloma. In the current study, we demonstrate 5T myeloma establishment in recombination activating gene 2 (RAG-2)-deficient mice, which have improper B- and T-cell development. Importantly, these mice can be easily bred with genetically modified mice to generate double knockout mice, allowing manipulation of the host microenvironment at a molecular level. Inoculation of 5TGM1 myeloma cells into RAG-2−/− mice resulted in myeloma development, which was associated with tumor growth within bone and an osteolytic bone disease, as assessed by microcomputed tomography (microCT), histology and histomorphometry. Myeloma-bearing RAG-2−/− mice displayed many features that were similar to both human myeloma and the original Radl 5T model. To demonstrate the use of this model, we have examined the effect of host-derived matrix metalloproteinase 9 (MMP-9) in the development of myeloma in vivo. Inoculation of 5TGM1 myeloma cells into mice that are deficient in RAG-2 and MMP-9 resulted in a reduction in both tumor burden and osteolytic bone disease when compared with RAG-2-deficient wild-type myeloma-bearing mice. The establishment of myeloma in RAG-2−/− mice permits molecular examination of the host contribution to myeloma pathogenesis in vivo.

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“…15 Although the exact mechanisms for this are unclear, apomine appears to exert its effects by mimicking the actions of farnesol, [16][17][18] a metabolite of the mevalonate pathway intermediate farnesyl pyrophosphate, which plays a role in feedback regulation of HMG-CoA reductase activity. 19 It is interesting to note that apomine exerts antitumor activity in vitro 16,20 and in the 5T2MM mouse myeloma model 21 through mechanisms distinct from the down-regulation of HMG-CoA reductase, most likely involving inhibition of the phosphatidylcholine synthesis pathway, 18 again mimicking the actions of farnesol. [22][23][24] In a phase 1 study of apomine in patients with epithelial ovarian cancer, at the initial dose level (125 mg/m 2 daily), the plasma concentration on day 14 of the treatment cycle was 16.4 mg/mL (29.1 mM), and the time to reach it was 3.1 AE 2.3 hours.…”

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confidence: 99%

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Moriceau

Roelofs

Brion

et al. 2011

Cancer

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BACKGROUND: Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis. METHODS: The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines. RESULTS: Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used. CONCLUSIONS: The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma. Cancer 2012;118:750-

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Apomine™, an inhibitor of HMG‐CoA‐reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo

Cited by 21 publications

References 30 publications

Differential Effect of Doxorubicin and Zoledronic Acid on Intraosseous versus Extraosseous Breast Tumor Growth In vivo

Differential Effect of Doxorubicin and Zoledronic Acid on Intraosseous versus Extraosseous Breast Tumor Growth In vivo

A murine model of myeloma that allows genetic manipulation of the host microenvironment

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

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