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Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo

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Tumor Biology

Abstract

Lung cancer is a global health problem. The search for new therapeutic approaches for the treatment of lung cancer is important. Here, we reported that the AKT inhibitor perifosine and the MEK\ERK inhibitor MEK-162 synergistically induced lung cancer cell (A549 and H460 lines) growth inhibition and apoptosis. The combined efficiency was significantly higher than either agent alone. For the molecular study, perifosine and MEK-162 worked together to concurrently block AKT, mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and MEK-ERK signalings in lung cancer cells, while either agent alone only affected one or two signalings with lower efficiency. In vivo, MEK-162 and perifosine co-administration dramatically inhibited A549 lung cancer xenograft growth, without inducing apparent toxicities. The synergistic activity in vivo was again superior than either agent alone. Thus, perifosine and MEK-162 combination is biologically plausible by acting through effects on different proliferation and survival-related signaling pathways. Our in vitro and in vivo results support the feasibility of investigating the synergism regimen in clinical tests.

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Abbreviations

ELISA:

Enzyme-linked immunosorbent assay

ERK:

Extracellular regulated kinase

FBS:

Fetal bovine serum

mTOR:

Mammalian target of rapamycin

mTORC1:

Mammalian target of rapamycin (mTOR) complex 1

NSCLCs:

Non-small cell lung cancers

PI3K:

Phosphatidylinositol-3-kinase

PVDF:

Polyvinylidene fluoride

RCC:

Renal cell carcinoma

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Acknowledgments

This work is supported by the National Science Foundation of China.

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Authors and Affiliations

  1. Department of Respiratory Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou, China

    Jianli Zhang & Yue Hong

  2. Department of Pediatrics, the First Affiliated Hospital of Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310003, China

    Jie Shen

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  1. Jianli Zhang
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  2. Yue Hong
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Correspondence to Jie Shen.

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Zhang, J., Hong, Y. & Shen, J. Combination treatment with perifosine and MEK-162 demonstrates synergism against lung cancer cells in vitro and in vivo. Tumor Biol. 36, 5699–5706 (2015). https://doi.org/10.1007/s13277-015-3244-2

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  • DOI: https://doi.org/10.1007/s13277-015-3244-2

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