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Molecular mechanism mediating cytotoxic activity of axitinib in sunitinib-resistant human renal cell carcinoma cells

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Abstract

Purpose

This study aimed to clarify the molecular mechanism mediating the cytotoxicity of axitinib, a selective inhibitor of the vascular endothelial growth factor receptor (VEGFR), in sunitinib-resistant renal cell carcinoma (RCC).

Methods

In our previous study (Sakai et al. in BJU Int 112:E211–E220, 2013), a human RCC cell line, ACHN, resistant to sunitinib (ACHN/R), was developed from a parental cell line (ACHN/P). Differences in molecular phenotypes following treatment with sunitinib or axitinib between these two cell lines were compared.

Results

ACHN/R showed an approximately fivefold higher IC50 of sunitinib than ACHN/P; however, there was no significant difference in the sensitivity to axitinib between these two cell lines. In ACHN/R, despite the lack of a difference in the phosphorylated (p)-Akt or STAT-3 expression between treatment with sunitinib and axitinib, the expression of p-p44/42 mitogen-activated protein kinase (MAPK) and p-VEGFR-2 after treatment with axitinib was markedly down-regulated compared with those after treatment with sunitinib. Furthermore, additional treatment of ACHN/R with an inhibitor of MAPK kinase significantly enhanced the cytotoxic activity of sunitinib, but not that of axitinib. In vivo growth of ACHN/R in nude mice after treatment with axitinib was significantly inhibited compared with that following treatment with sunitinib, accompanying the marked inhibition of angiogenesis.

Conclusions

Antitumor activity of axitinib in RCC cells even after the acquisition of resistance to sunitinib could be explained, at least in part, by the inactivation of p44/42 MAPK and VEGFR-2, which were persistently phosphorylated in sunitinib-resistant RCC cells under treatment with sunitinib.

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Authors and Affiliations

  1. Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    A. Miyazaki, H. Miyake & M. Fujisawa

Authors
  1. A. Miyazaki
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  2. H. Miyake
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  3. M. Fujisawa
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Corresponding author

Correspondence to H. Miyake.

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Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All applicable international, national and institutional guidelines for the care and use of animals were followed.

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Miyazaki, A., Miyake, H. & Fujisawa, M. Molecular mechanism mediating cytotoxic activity of axitinib in sunitinib-resistant human renal cell carcinoma cells. Clin Transl Oncol 18, 893–900 (2016). https://doi.org/10.1007/s12094-015-1457-x

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  • DOI: https://doi.org/10.1007/s12094-015-1457-x

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