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Article

Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib

  • Authors:
    • Bi‑Sheng Liu
    • Xin‑Yu Dai
    • Hong‑Wei Xia
    • Huan‑Ji Xu
    • Qiu‑Lin Tang
    • Qi‑Yong Gong
    • Yong‑Zhan Nie
    • Feng Bi
  • View Affiliations / Copyright

    Affiliations: Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China, State Key Laboratory of Cancer Biology and Xijing Hospital of Digest Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China
  • Pages: 4023-4029
    |
    Published online on: August 9, 2018
       https://doi.org/10.3892/mmr.2018.9371
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Abstract

Dysregulation of epidermal growth factor receptor (EGFR) signaling is responsible for the resistance to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, and is thereby associated with the progression of tumors in non‑small cell lung cancers (NSCLCs). Immunoblotting results revealed that geranylgeranyl transferase 1 inhibitor (GGTI)‑298, a geranylgeranyl transferase 1 inhibitor with potential antitumor effects, effectively inhibited the phosphorylation of EGFR and its downstream target protein kinase B (AKT). A combination of gefitinib and GGTI‑298 amplified the inhibition of the EGFR‑AKT signaling pathway. In addition, GGTI‑298 treatment produced a synergistic effect on the inhibition of proliferation as indicated by the combination index values of <1 when combined with gefitinib in the NSCLC cell lines HCC827 and A549. These synergistic effects were also observed to induce apoptosis and migration inhibition. Further mechanistic studies demonstrated that GGTI‑298 inhibited the activity of Ras homolog family member A (RhoA), and downregulation of RhoA with small interfering RNA impaired the phosphorylation of EGFR, which suggested that EGFR inhibition by GGTI‑298 may be exerted mainly through RhoA mediation. These results presented a novel, promising therapeutic strategy involving a combination of two drugs for targeting EGFR signaling in lung cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Liu BS, Dai XY, Xia HW, Xu HJ, Tang QL, Gong QY, Nie YZ and Bi F: Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib. Mol Med Rep 18: 4023-4029, 2018.
APA
Liu, B., Dai, X., Xia, H., Xu, H., Tang, Q., Gong, Q. ... Bi, F. (2018). Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib. Molecular Medicine Reports, 18, 4023-4029. https://doi.org/10.3892/mmr.2018.9371
MLA
Liu, B., Dai, X., Xia, H., Xu, H., Tang, Q., Gong, Q., Nie, Y., Bi, F."Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib". Molecular Medicine Reports 18.4 (2018): 4023-4029.
Chicago
Liu, B., Dai, X., Xia, H., Xu, H., Tang, Q., Gong, Q., Nie, Y., Bi, F."Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib". Molecular Medicine Reports 18, no. 4 (2018): 4023-4029. https://doi.org/10.3892/mmr.2018.9371
Copy and paste a formatted citation
x
Spandidos Publications style
Liu BS, Dai XY, Xia HW, Xu HJ, Tang QL, Gong QY, Nie YZ and Bi F: Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib. Mol Med Rep 18: 4023-4029, 2018.
APA
Liu, B., Dai, X., Xia, H., Xu, H., Tang, Q., Gong, Q. ... Bi, F. (2018). Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib. Molecular Medicine Reports, 18, 4023-4029. https://doi.org/10.3892/mmr.2018.9371
MLA
Liu, B., Dai, X., Xia, H., Xu, H., Tang, Q., Gong, Q., Nie, Y., Bi, F."Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib". Molecular Medicine Reports 18.4 (2018): 4023-4029.
Chicago
Liu, B., Dai, X., Xia, H., Xu, H., Tang, Q., Gong, Q., Nie, Y., Bi, F."Geranylgeranyl transferase 1 inhibitor GGTI‑298 enhances the anticancer effect of gefitinib". Molecular Medicine Reports 18, no. 4 (2018): 4023-4029. https://doi.org/10.3892/mmr.2018.9371
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