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<p>Cutaneous T-cell lymphomas (CTCLs) are a rare and heterogeneous subset of skin-localized, non-Hodgkin lymphomas. Our aim was to evaluate the in vitro antitumor activity of the multi-kinase inhibitor linifanib, either alone or in combination with metronomic vinorelbine (mVNR) or etoposide (mETO), on CTCL cells. In vitro proliferation assay and Luminex analysis showed that long-term, daily exposure of linifanib significantly inhibited the proliferation of the human CTCL cell line HH, in a concentration-dependent manner (IC<sub>50</sub> = 48.4 ± 20.4&#xa0;nM) and the phosphorylation of AKT/mTOR signaling pathway. The concomitant exposure of linifanib plus mVNR or mETO resulted in a strong synergism, with combination index values &lt; 1. Linifanib significantly increased the VNR and ETO intracellular concentrations in HH cells, evaluated by UPLC-HRMS technology, and strongly reduced the <i>ABCB1</i> and <i>ABCG2</i> gene expression in HH. In conclusion, we reported a striking antitumor activity of daily, long-term linifanib and a clear synergistic effect when administered in combination with mCHEMO on CTCL cells, as a promising base for future clinical approaches in T-cell lymphomas.</p> Graphical Abstract <p></p>

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Linifanib alone and in combination with metronomic chemotherapy is active on cutaneous T-cell lymphoma cells by targeting the AKT/mTOR signaling pathway

  • 期刊论文

  • 发表日期：

    2025年1月17日

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  • Marta Banchi,
  • Maria Christina Cox,
  • Arianna Bandini,
  • Paola Orlandi,
  • Costanza Tacchi,
  • Fabio Stefanelli,
  • Silvio Chericoni,
  • Guido Bocci

摘要

Cutaneous T-cell lymphomas (CTCLs) are a rare and heterogeneous subset of skin-localized, non-Hodgkin lymphomas. Our aim was to evaluate the in vitro antitumor activity of the multi-kinase inhibitor linifanib, either alone or in combination with metronomic vinorelbine (mVNR) or etoposide (mETO), on CTCL cells. In vitro proliferation assay and Luminex analysis showed that long-term, daily exposure of linifanib significantly inhibited the proliferation of the human CTCL cell line HH, in a concentration-dependent manner (IC50 = 48.4 ± 20.4 nM) and the phosphorylation of AKT/mTOR signaling pathway. The concomitant exposure of linifanib plus mVNR or mETO resulted in a strong synergism, with combination index values < 1. Linifanib significantly increased the VNR and ETO intracellular concentrations in HH cells, evaluated by UPLC-HRMS technology, and strongly reduced the ABCB1 and ABCG2 gene expression in HH. In conclusion, we reported a striking antitumor activity of daily, long-term linifanib and a clear synergistic effect when administered in combination with mCHEMO on CTCL cells, as a promising base for future clinical approaches in T-cell lymphomas.

Graphical Abstract