Dual Protein Farnesyltransferase−Geranylgeranyltransferase-I Inhibitors as Potential Cancer Chemotherapeutic Agents

Desolms, S. J.; Ciccarone, Terrence M.; MacTough, Suzanne C.; Shaw, A.; Buser, Carolyn A.; Ellis-Hutchings, Michelle; Fernandes, Christine; Hamilton, Kelly; Huber, Hans E.; Kohl, Nancy E.; Lobell, Robert B.; Robinson, R.; Tsou, Nancy N.; Walsh, Eileen S.; Graham, Samuel; Beese, L.S.; Taylor, Jeffrey S.

doi:10.1021/jm020587n

Cited by 58 publications

(36 citation statements)

References 17 publications

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“…Hence, the degree of inhibition of this pathway may be critical for cell survival with incomplete inhibition of prenylation as seen with statins not being able to demonstrate in man significant cytotoxic effect by itself, while highly efficient inhibitory agents of the farnesyl and geranylgeranyl pathways are toxic [82]. In our studies, reversal of inhibition of prenylation by the addition of either farnesyl pyrophosphate or geranylgeranyl pyrophosphate was incomplete at a dosage of drugs which caused a moderate cell kill (IC 50 ) but was unable to reverse the cytotoxicity at high cell kill (IC 70 ) implying that the combination effect observed may be due to more than one mechanism.…”

Section: Resultsmentioning

confidence: 99%

Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro

Budman

Tai

Calabro

2006

Breast Cancer Res Treat

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The combination of anticancer drugs used in the clinic has been based upon empiricism, and the potential permutations of currently available drugs overwhelm the clinical trials system. Recently, investigators have suggested that the combination of a blockade of vital signal transduction pathways in combination with more standard therapy might enhance anticancer effect. Using a panel of breast cancer cell lines and isobologram median effect analysis, a method of determining synergism or antagonism of drugs, we have investigated in vitro potentially clinically useful combinations of agents with the human cell lines MCF7/wt, MCF7/adr, BT474, and SK-BR-3 grown in log phase. Results were confirmed by curve shift analysis. Cells were exposed to the agent(s) for 72 h and then analyzed for cytotoxicity using a MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl-tetrazolium bromide) assay. Fluvastatin, an inhibitor of prenylation with excellent tolerability in man, was chosen to disrupt signal transduction pathways and thus potentially enhance the effect of more traditional anticancer agents. Anticancer agents tested were cytotoxics used in the treatment of breast cancer, trastuzumab, and rapamycin as an inhibitor of the AKT pathway. Fluvastatin combined with trastuzumab demonstrates global synergy of cytotoxic effect that is confirmed by apoptosis assay. These effects could only be partially reversed by adding farnesol or geranylgeraniol to restore prenylation. Epirubicin is also synergistic with fluvastatin in three of the four cell lines. Rapamycin, an inhibitor of MTOR, was synergistic with fluvastatin in two of the four cell lines and antagonistic in two other cell lines. The combination of fluvastatin or another inhibitor of prenylation and trastuzumab may be attractive for clinical development as the effect of trastuzumab in Her2/neu positive breast tumors is incomplete as a single agent.

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Section: Resultsmentioning

confidence: 99%

Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro

Budman

Tai

Calabro

2006

Breast Cancer Res Treat

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“…These G proteins are acylated and/or prenylated and these modifications act as membrane anchors for ras. Prenylation is catalysed by farnesyl transferase or geranylgeranyl transferase I that transfer to the protein substrate a farnesyl group or a geranylgeranyl group, respectively (DeSolms et al, 2003). The synthesis of both farnesyl and geranylgeranyl residues requires the activity of the farnesyl pirophosphate synthase, the upstream enzyme involved in the cholesterol synthesis chain (Schafer and Rine, 1992).…”

Section: Introductionmentioning

confidence: 99%

The farnesyl transferase inhibitor R115777 (Zarnestra®) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa®) and Pamidronate

et al. 2004

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Pamidronate (PAM) and zoledronic acid (ZOL) are aminobisphosphonates (BPs) able to affect the isoprenylation of intracellular small G proteins. We have investigated the antitumor activity of BPs and R115777 farnesyl transferase inhibitor (FTI) against epidermoid cancer cells. In human epidermoid head and neck KB and lung H1355 cancer cells, 48 h exposure to PAM and ZOL induced growth inhibition (IC 50 25 and 10 lM, respectively) and apoptosis and abolished the proliferative and antiapoptotic stimuli induced by epidermal growth factor (EGF). In these experimental conditions, ZOL induced apoptosis through the activation of caspase 3 and a clear fragmentation of PARP was also demonstrated. A strong decrease of basal ras activity and an antagonism on its stimulation by EGF was recorded in the tumor cells exposed to BPs. These effects were paralleled by impaired activation of the survival enzymes extracellular signal regulated kinase 1 and 2 (Erk-1/2) and Akt that were not restored by EGF. Conversely, farnesol induced a recovery of ras activity and antagonized the proapoptotic effects induced by BPs. The combined treatment with BPs and R115777 resulted in a strong synergism both in growth inhibition and apoptosis in KB and H1355 cells. The synergistic activity between the drugs allowed BPs to produce tumor cell growth inhibition and apoptosis at in vivo achievable concentrations (0.1 lmolar for both drugs). Moreover, the combination was highly effective in the inhibition of ras, Erk and Akt activity, while farnesol again antagonized these effects. In conclusion, the combination of BPs and FTI leads to enhanced antitumor activity at clinically achievable drug concentrations that resides in the inhibition of farnesylationdependent survival pathways and warrants further studies for clinical translation.

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“…These G proteins are acylated and/or prenylated, and these modifications act as membrane anchors for ras. Prenylation is catalyzed by farnesyl transferase (FT) or geranylgeranyl transferase I that transfer to the protein substrate a farnesyl group or a geranylgeranyl group, respectively (DeSolms et al, 2003). The synthesis of both farnesyl and geranylgeranyl residues requires the activity of the farnesyl pyrophosphate synthase, the upstream enzyme involved in the cholesterol synthesis chain (Schafer and Rine, 1992).…”

mentioning

confidence: 99%

R115777 (Zarnestra®)/Zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl‐2 and bad phosphorylation

Caraglia

Marra

Leonetti

et al. 2006

Journal Cellular Physiology

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Zoledronic acid (ZOL) has proved activity in bone metastases from prostate cancer through inhibition of mevalonate pathway and of prenylation of intracellular proteins. We have reported that ZOL synergizes with R115777 farnesyltransferase inhibitor (FTI, Zarnestra) in inducing apoptosis and growth inhibition on epidermoid cancer cells. Here, we have studied the effects of the combination of these agents in prostate adenocarcinoma models and, specifically, on androgen-independent (PC3 and DU145) and -dependent (LNCaP) prostate cancer cell lines. We have found that ZOL and R115777 were synergistic in inducing both growth inhibition and apoptosis in prostate adenocarcinoma cells. These effects were paralleled by disruption of Ras-->Erk and Akt survival pathways, consequent decreased phosphorylation of both mitochondrial bcl-2 and bad proteins, and caspase activation. Finally, ZOL/R115777 combination induced cooperative effects also in vivo on tumor growth inhibition of prostate cancer xenografts in nude mice with a significant survival increase. These effects were paralleled by enhanced apoptosis and inactivation of both Erk and Akt. In conclusions, the combination between ZOL and FTI leads to enhanced anti-tumor activity in human prostate adenocarcinoma cells likely through a more efficacious inhibition of ras-dependent survival pathways and consequent bcl-related proteins-dependent apoptosis.

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Dual Protein Farnesyltransferase−Geranylgeranyltransferase-I Inhibitors as Potential Cancer Chemotherapeutic Agents

Cited by 58 publications

References 17 publications

Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro

Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro

The farnesyl transferase inhibitor R115777 (Zarnestra®) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa®) and Pamidronate

R115777 (Zarnestra®)/Zoledronic acid (Zometa®) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl‐2 and bad phosphorylation

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