Synergistic tumor suppression by a Perilla frutescens-derived methoxyflavanone and anti-cancer tyrosine kinase inhibitors in A549 human lung adenocarcinoma
- 307 Downloads
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.
KeywordsA549 cells Lung cancer Methoxyflavanone Perilla frutescens Tyrosine kinase inhibitors
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Gridelli C, De Marinis F, Cappuzzo F, Di Maio M, Hirsch FR, Mok T, Morgillo F, Rosell R, Spigel DR, Yang JC, Ciardiello F (2014) Treatment of advanced non–small-cell lung cancer with epidermal growth factor receptor (EGFR) mutation or ALK gene rearrangement: results of an international expert panel meeting of the Italian Association of Thoracic Oncology. Clin Lung Cancer 15:173–181CrossRefPubMedGoogle Scholar
- Ito K, Semba T, Uenaka T, Wakabayashi T, Asada M, Funahashi Y (2014) Enhanced anti-angiogenic effect of E7820 in combination with erlotinib in epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer xenograft models. Cancer Sci 105:1023–1031CrossRefPubMedPubMedCentralGoogle Scholar
- Kamei R, Fujimura T, Matsuda M, Kakihara K, Hirakawa N, Baba K, Ono K, Arakawa K, Kawamoto S (2017) A flavanone derivative from the Asian medicinal herb (Perilla frutescens) potently suppresses IgE-mediated immediate hypersensitivity reactions. Biochem Biophys Res Commun 483:674–679CrossRefPubMedGoogle Scholar
- Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sánchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M, Spanish Lung Cancer Group (2009) Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 361:958–967CrossRefPubMedGoogle Scholar