The Mevalonate/Isoprenoid Pathway Inhibitor Apomine (SR-45023A) Is Antiproliferative and Induces Apoptosis Similar to Farnesol

Flach, Jean; Antoni, Isabelle; Villemin, Pascal; Bentzen, C.; Niesor, Eric J.

doi:10.1006/bbrc.2000.2421

Cited by 31 publications

(35 citation statements)

References 28 publications

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“…This confirms the findings from previous studies indicating that apomine exerts its proapoptotic activity through mechanisms distinct from the inhibition of HMG-CoA reductase. 16,18 Instead, apomine most likely induces apoptosis through inhibition of the phosphatidylcholine synthesis pathway by acting as a synthetic mimetic of farnesol. 16,18 When combining apomine and lovastatin treatment of osteosarcoma cells, the drug combination resulted in decreased HMG-CoA reductase protein levels and synergistic increases in the accumulation of unprenylated Rap1A, indicative of a decrease in HMG-CoA reductasemediated mevalonate synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…16,18 Instead, apomine most likely induces apoptosis through inhibition of the phosphatidylcholine synthesis pathway by acting as a synthetic mimetic of farnesol. 16,18 When combining apomine and lovastatin treatment of osteosarcoma cells, the drug combination resulted in decreased HMG-CoA reductase protein levels and synergistic increases in the accumulation of unprenylated Rap1A, indicative of a decrease in HMG-CoA reductasemediated mevalonate synthesis. Furthermore, the synergistic effects on protein prenylation, as well as viability and apoptosis, all could be prevented by the addition of either mevalonate or geranylgeraniol (the latter was converted to geranylgeranyl pyrophosphate, the downstream isoprenoid lipid used as substrate for the prenylation of proteins).…”

Section: Discussionmentioning

confidence: 99%

“…14 However, apomine acts to down-regulate HMG-CoA reductase protein levels by increasing the proteasomal degradation rate of this enzyme. 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.…”

mentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Moriceau

Roelofs

Brion

et al. 2011

Cancer

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“…[7][8][9] Their HMG-CoA reductases came from Chinese hamster ovary cell, Met-18b-2 cell and HL60 etc. They are class I HMG-CoA reductase.…”

Section: Introductionmentioning

confidence: 99%

Effect of farnesol on mevalonate pathway of Staphylococcus aureus

et al. 2011

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To investigate the mechanism of action by which farnesol functions as an antibacterial agent and inhibits Staphylococcus aureus growth, the growth rates of S. aureus cultured in farnesol versus S. aureus cultured in farnesol and supplemented with 3-hydroxy-3-methylglutaryl (HMG)-CoA or mevalonate were compared. The investigation was designed to observe whether farnesol affected on the mevalonate pathway by using the intermediate metabolites of the pathway. The resulting growth curves demonstrated that mevalonate reduced the antibacterial activity of farnesol, but HMG-CoA did not inhibit farnesol. These results suggest that farnesol affects the mevalonate pathway. Moreover, farnesol inhibited HMG-CoA reductase activity in an in vitro enzymatic assay.

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DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress‐induced apoptosis

Stasi

Vallacchi

Campi

et al. 2005

Intl Journal of Cancer

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The DHCR24 gene encoding for the 3β‐hydroxysterol Δ24‐reductase, an oxidoreductase involved in cholesterol biosynthesis, was isolated by subtractive hybridization as highly expressed in a short‐term melanoma cell line derived from a cutaneous metastases (S/M2) compared to that obtained from the autologous primary tumor (S/P). DHCR24 (alias seladin‐1, diminuto/dwarf1 homolog) has been reported to act as an antiapoptotic factor in neurons. Gene expression analysis by Northern blot confirmed that DHCR24 was 5‐fold upregulated in S/M2 compared to S/P cells. High levels of DHCR24 gene expression were detected in 13/25 melanoma metastases and in 1/7 primary melanomas by real‐time PCR, indicating that upregulation of this gene may occur in melanoma progression. In S/M2 cells, high DHCR24 gene expression associated with resistance to apoptosis triggered by oxidative stress induced by exposure to hydrogen peroxide. DHCR24 gene transfer was shown to protect melanoma cells from H2O2‐induced cytotoxicity. Although higher cholesterol levels were shown in S/M2 cells compared to S/P cells, DHCR24 gene transfer did not increase cholesterol content. To evaluate whether DHCR24 acts as an antiapoptotic factor in melanoma metastases, the cytotoxic effect of chemotherapeutic agents was tested in DHCR24 transfectants and in the presence of a DHCR24 inhibitor, U18666A. High DHCR24 gene expression in transfectants did not result in a higher resistance to cytotoxic agents; treatment with U18666A was cytotoxic in S/P cells with a lower DHCR24 content and showed additive cytotoxic effect only when associated with H2O2 and not with cysplatin or etoposide, indicating that the DHCR24 protective effect is exerted through an oxidative stress‐specific mechanism. © 2005 Wiley‐Liss, Inc.

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The Mevalonate/Isoprenoid Pathway Inhibitor Apomine (SR-45023A) Is Antiproliferative and Induces Apoptosis Similar to Farnesol

Cited by 31 publications

References 28 publications

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth

Effect of farnesol on mevalonate pathway of Staphylococcus aureus

DHCR24 gene expression is upregulated in melanoma metastases and associated to resistance to oxidative stress‐induced apoptosis

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