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Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing

1
Department of Molecular Cancer Science, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
2
Department of Clinical Oncology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
3
Department of Ophthalmology and Visual Sciences, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
4
Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan
*
Authors to whom correspondence should be addressed.
Biomedicines 2020, 8(8), 273; https://doi.org/10.3390/biomedicines8080273
Received: 16 June 2020 / Revised: 31 July 2020 / Accepted: 1 August 2020 / Published: 5 August 2020
(This article belongs to the Section Cancer Biology and Therapeutics)
Osimertinib, which is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is an important anticancer drug because of its high efficacy and excellent safety profile. However, resistance against osimertinib is inevitable; therefore, therapeutic strategies to overcome the resistance are needed. Doxazosin, a classic quinazoline-based alpha 1-adrenoceptor antagonist is used to treat hypertension and benign prostatic hyperplasia with a known safety profile. The anticancer effects of doxazosin have been examined in various types of malignancies from the viewpoint of drug repositioning or repurposing. However, it currently remains unclear whether doxazosin sensitizes cancer cells to osimertinib. Herein, we demonstrated that doxazosin induced autophagy and enhanced the anticancer effects of osimertinib on the cancer cells and cancer stem cells of non-small cell lung cancer, pancreatic cancer, and glioblastoma at a concentration at which the growth of non-tumor cells was not affected. The osimertinib-sensitizing effects of doxazosin were suppressed by 3-methyladenine, an inhibitor of autophagy, which suggested that the effects of doxazosin were mediated by autophagy. The present study provides evidence for the efficacy of doxazosin as a combination therapy with osimertinib to overcome resistance against osimertinib. View Full-Text
Keywords: drug resistance; doxazosin; osimertinib; autophagy; drug repositioning; drug repurposing; cancer stem cells drug resistance; doxazosin; osimertinib; autophagy; drug repositioning; drug repurposing; cancer stem cells
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Suzuki, S.; Yamamoto, M.; Sanomachi, T.; Togashi, K.; Sugai, A.; Seino, S.; Okada, M.; Yoshioka, T.; Kitanaka, C. Doxazosin, a Classic Alpha 1-Adrenoceptor Antagonist, Overcomes Osimertinib Resistance in Cancer Cells via the Upregulation of Autophagy as Drug Repurposing. Biomedicines 2020, 8, 273.

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