Synergistic tumor suppression by a Perilla frutescens-derived methoxyflavanone and anti-cancer tyrosine kinase inhibitors in A549 human lung adenocarcinoma

Abstract

Anti-cancer tyrosine kinase inhibitors (TKIs) are effective in many types of cancers including non-small cell lung cancer, while appearance of TKI-resistant tumors suggests a need for the development of their potentiation strategies. We have previously shown that a methoxyflavanone derivative from the Asian medicinal herb Perilla frutescens (Perilla-derived methoxyflavanone; PDMF) shows a prominent anti-tumor activity against A549 human lung adenocarcinoma. Here we show that PDMF and anti-cancer TKIs (nilotinib, bosutinib, dasatinib, and ponatinib) synergistically suppress proliferation of A549 cells. Flow cytometric analysis indicated that co-stimulation with nilotinib (4 μM) and PDMF induced G2/M cell cycle arrest in low PDMF doses (10–50 μM), whereas this combination triggered de novo G1 arrest in higher PDMF dosages (50–125 μM). We also found that co-administration with nilotinib and PDMF significantly suppressed in vivo tumorigenicity of A549 cells in athymic nude mice.

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Acknowledgements

This work was financially supported by the Mishima Food Co., Ltd (to S. Kawamoto). N. Hirakawa and K. Baba are employees of the Mishima Food Co., Ltd. A. A. Abd El-Hafeez was supported by the Ministry of Education, Culture, Sports, Science, and Technology, MEXT, Japan.

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Correspondence to Seiji Kawamoto.

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Abd El-Hafeez, A.A., Fujimura, T., Kamei, R. et al. Synergistic tumor suppression by a Perilla frutescens-derived methoxyflavanone and anti-cancer tyrosine kinase inhibitors in A549 human lung adenocarcinoma. Cytotechnology 70, 913–919 (2018). https://doi.org/10.1007/s10616-017-0124-1

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Keywords

  • A549 cells
  • Lung cancer
  • Methoxyflavanone
  • Perilla frutescens
  • Tyrosine kinase inhibitors