Epidermal growth factor receptor-targeted therapy potentiates lovastatin-induced apoptosis in head and neck squamous cell carcinoma cells

Mantha, Angela J.; McFee, Kathryn E.; Niknejad, Nima; Goss, Glenwood D.; Lorimer, Ian A. J.; Dimitroulakos, Jim

doi:10.1007/s00432-003-0490-2

Cited by 33 publications

(45 citation statements)

References 43 publications

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“…Lovastatin potentiated the antitumor effects of cisplatin in cellular and murine models of melanoma (Feleszko et al, 1998), increasing, at least partially, the apoptotic effect of oxaliplatin in human head and neck squamous cell carcinoma (SCC) (Mantha et al, 2003). In human colon cancer cell lines, the pretreatment with lovastatin increased the apoptotic death induced by cisplatin (Agarwal et al, 1999a).…”

Section: Statins In Cancer Treatmentmentioning

confidence: 99%

“…In human colon cancer cell lines (Agarwal et al, 1999a), but not in breast cancer cell lines (Mantha et al, 2003), the cytotoxic effects of 5-fluorouracil (5-FU) were potentiated by the combined use of lovastatin. Similar increases in 5-FU antiproliferative effects were also ob-STATINS AND CANCER: PROS AND CONS tained with atorvastatin or simvastatin combined with 5-FU in human non-small-cell lung cancer cell lines (Roudier et al, 2006) or in human myeloid leukemia cell lines (Ahn et al, 2008b), respectively.…”

Section: Statins In Cancer Treatmentmentioning

confidence: 99%

“…The inhibition of NF-B and the synchronized arrest in different phases of the cell cycle have been also suggested as the main cellular mechanisms through which synergistic effects of statins (mainly lovastatin and simvastatin) and paclitaxel occurred (Holstein and Hohl, 2001a;Ahn et al, 2008b). These combinations efficaciously potentiated the paclitaxel-induced cytotoxic effects in human leukemic cells (Holstein and Hohl, 2001b;Ahn et al, 2008b) but not in human breast cancer cell lines and in head and neck SCC cell lines (Mantha et al, 2003).…”

Section: Statins In Cancer Treatmentmentioning

confidence: 99%

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Section: Statins In Cancer Treatmentmentioning

confidence: 99%

Section: Statins In Cancer Treatmentmentioning

confidence: 99%

Section: Statins In Cancer Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

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Gangemi³

et al. 2011

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“…EGFR inhibitors therefore seem very promising, but there are still a large number of questions about how to maximize their potential in cancer therapy. We have shown in preclinical studies that combining EGFR inhibitors with inhibitors of the mevalonate pathway may enhance their efficacy (16,17). This review describes the rationale and potential of using these inhibitors in combination to treat cancer.…”

Section: The Egfr As Atherapeutictargetmentioning

confidence: 99%

Strategies to Enhance Epidermal Growth Factor Inhibition: Targeting the Mevalonate Pathway

Dimitroulakos

Lorimer

Goss

2006

Clinical Cancer Research

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Mevalonate metabolites play an essential role in transducing epidermal growth factor (EGF) receptor (EGFR)^mediated signaling, as several of these metabolites are required for the function of this receptor and the components of its signaling cascades. Thus, the depletion of mevalonate metabolites may have a significant effect on EGFR function. Lovastatin is a specific and potent inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Targeting 3-hydroxy-3-methylglutaryl CoA reductase using lovastatin induces a potent tumor-specific apoptotic response in a variety of tumor types at therapeutically achievable levels of this drug. The effects of lovastatin on EGFR function and the potential combination effects with EGFR tyrosine kinase inhibitors, such as gefitinib, were evaluated. Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation and its downstream signaling cascades by 24 hours. Combining lovastatin and gefitinib showed enhanced inhibition and cooperative cytotoxicity in a variety of cell lines that included all eight squamous cell carcinomas, four nonŝ mall cell lung carcinoma, and four colon carcinoma cell lines tested. Isobologram analyses confirmed that this combination was synergistic, inducing a potent apoptotic response. A phase I study has shown the safety and potential clinical benefit of high-dose lovastatin in patients with recurrent squamous cell carcinoma. The use of lovastatin, which is metabolized by CYP3A4, is contraindicated with drugs, such as gefitinib and erlotinib, which are also metabolized by CYP3A4 due to greatly enhanced toxicity. Rosuvastatin, a relatively novel potent mevalonate pathway inhibitor that is not metabolized significantly by CYP3A4, is a more appropriate statin to combine with either erlotinib or gefitinib. The combination of erlotinib and rosuvastatin has been proposed for a phase I/II study in advanced non^small cell lung carcinoma.The ErbB family of receptor proteins [ErbB1/epidermal growth factor (EGF) receptor (EGFR), ErbB2, ErbB3, and ErbB4] plays a key role in the growth, differentiation, migration, and cell survival of epithelial tissues (1, 2). These cell membrane receptors are functionally divided into three regions: an extracellular ligand-binding region, an intracellular region with tyrosine kinase activity and regulatory functions, and a region that spans the cell membrane and anchors the receptor to the cell (3). In the inactive state, each ErbB receptor exists as a monomer. Despite their high degree of structural homology, the ErbB receptors differ in their ligand specificities. EGFR, ErbB3, and ErbB4 are activated by a large family of ligands, with each receptor having differences in its ligand specificity (4).ErbB2 has no ligand but preexists in a conformation that allows it to heterodimerize with other ErbB family members (4). These ErbB2-containing heterodimers form the highest affinity binding sites for their respective ligands (4). Ligand binding to the EGFR promotes either hom...

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“…Targeting HMG-CoA reductase using lovastatin induces a potent tumor specific apoptotic response in a variety of tumor types including HNSCC-derived cell lines at therapeutically achievable levels of this drug (20,21). We recently showed that inhibiting EGFR function potentiated the apoptotic effects of lovastatin in HNSCC cells (22). The additive effects shown in HNSCC-derived cell lines suggested the possibility that these agents, although acting through distinct mechanisms, may share a common target.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor

Mantha

Hanson²,

Goss³

et al. 2005

Clinical Cancer Research

Self Cite

103

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Purpose: The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFRtargeted therapies.Experimental Design: In this study, we evaluated the effect of lovastatin on EGFR function and on gefitinib activity. Effects on EGFR function were analyzed by Western blot analysis using phosphospecific antibodies to EGFR, AKT, and extracellular signal-regulated kinase. Cytotoxic effects of lovastatin and/or gefitinib were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry.Results: Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation by 24 hours that was reversed by the coadministration of mevalonate. Combining lovastatin and gefitinib treatments showed enhanced inhibition of AKT activation by EGF in SCC9 cells. The combination of 10 Mmol/L lovastatin and 10 Mmol/L gefitinib treatments showed cooperative cytotoxicity in all 8 squamous cell carcinomas, 4 of 4 non -small cell lung carcinoma and 4 of 4 colon carcinoma cell lines tested. Isobologram and flow cytometric analyses of three representative cell lines with wild-type EGFR ATP binding sites confirmed that this combination was synergistic inducing a potent apoptotic response.Conclusions: Taken together, these results show that targeting the mevalonate pathway can inhibit EGFR function. They also suggest the potential utility of combining these clinically relevant therapeutic approaches.

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Epidermal growth factor receptor-targeted therapy potentiates lovastatin-induced apoptosis in head and neck squamous cell carcinoma cells

Abstract: These results demonstrated the ability of EGFR pathway inhibitors to potentiate lovastatin-induced apoptosis and suggested that lovastatin may target the EGFR pathway in HNSCC cells.

Cited by 33 publications

References 43 publications

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Strategies to Enhance Epidermal Growth Factor Inhibition: Targeting the Mevalonate Pathway

Targeting the Mevalonate Pathway Inhibits the Function of the Epidermal Growth Factor Receptor

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