Perifosine sensitizes curcumin-induced anti-colorectal cancer effects by targeting multiple signaling pathways both in vivo and in vitro

Authors

  • Min-Bin Chen,

    1. Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu Province, People's Republic of China
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    • M.-B.C. and X.Y.W. contributed equally to this work

  • Xiao-Yang Wu,

    1. Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu Province, People's Republic of China
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    • M.-B.C. and X.Y.W. contributed equally to this work

  • Guo-Qing Tao,

    1. Department of General Surgery, Oncology Center, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
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  • Chao-Ying Liu,

    1. Department of Medical Oncology, Oncology Center, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi City, Jiangsu Province, People's Republic of China
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  • Jian Chen,

    1. Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu Province, People's Republic of China
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  • Li-Qiang Wang,

    1. Department of Medical Oncology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu Province, People's Republic of China
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  • Pei-Hua Lu

    Corresponding author
    1. Department of General Surgery, Oncology Center, Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
    • Department of General Surgery, Oncology Center, Affiliated Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, Wuxi City 214023, Jiangsu Province, People's Republic of China
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    • Tel: 86-510-85350090, Fax: +86-510-82700778,


Abstract

Our study shows that coadministration of curcumin and an orally bioactive alkylphospholipid perifosine results in a significant increase in colorectal cancer cell apoptosis and a marked inhibition of cell growth both in vitro and in vivo. This novel combinatorial regimen leads to changes of multiple cell signaling pathways including inactivation of Akt and nuclear factor-κB as well as activation of c-Jun N-terminal kinases and endoplasmic reticulum stress. Further, perifosine and curcumin synergistically increase intracellular level of reactive oxygen species and ceramide, and downregulate the expression of cyclin D1 and Bcl-2 in colorectal cancer cells. These changes at molecular level together account for the cancer cell apoptosis and growth inhibition. We conclude that perifosine sensitizes colorectal cancer cells to curcumin by modulating multiple signaling pathways. Adding perifosine with curcumin may represent an effective therapy regimen against colorectal cancers, and possible other aggressive tumors.

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