Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Yuan Si; Jiu Wang; Xuewen Liu; Tong Zhou; Yuchen Xiang; Te Zhang; Xianhui Wang; Tingting Feng; Li Xu; Qingqing Yu; Huzi Zhao; Ying Liu

doi:10.3389/fphar.2019.01503

Ethoxysanguinarine, a Novel Direct Activator of AMP-Activated Protein Kinase, Induces Autophagy and Exhibits Therapeutic Potential in Breast Cancer Cells

Front Pharmacol. 2020 Jan 8:10:1503. doi: 10.3389/fphar.2019.01503. eCollection 2019.

Authors

Yuan Si^{1

2}, Jiu Wang^{1

3}, Xuewen Liu^{1

2}, Tong Zhou^{1

2}, Yuchen Xiang^{1

2}, Te Zhang^{2

4}, Xianhui Wang², Tingting Feng⁴, Li Xu², Qingqing Yu², Huzi Zhao^{1

2}, Ying Liu^{1

2

3

4}

Affiliations

¹ Laboratory of Molecular Target Therapy of Cancer, Institute of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
² Laboratory of Molecular Target Therapy of Cancer, Biomedical Research Institute, Hubei University of Medicine, Shiyan, China.
³ Hubei Key Laboratory of Wudang Local Chinese Medicine Research and Institute of Medicinal Chemistry, Hubei University of Medicine, Shiyan, China.
⁴ Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China.

Abstract

Ethoxysanguinarine (Eth) is a benzophenanthridine alkaloid extracted from Macleaya cordata (Willd) R. Br. It possesses antibacterial and antiviral activities and offers therapeutic benefits for the treatment of respiratory syndrome virus-induced cytopathic effects. However, the effect of Eth on human tumors and its pharmacological effects remain to be elucidated, together with its cellular target. Here, we examined the effects of Eth on breast cancer (BC) cells. We found that at low doses, Eth strongly inhibited the viability of BC cell lines and induced autophagy. Mechanistic studies showed that Eth induced autophagy by upregulating the activity of the AMP-activated protein kinase (AMPK). The AMPK inhibitor compound C significantly attenuated Eth-induced autophagy and inhibited proliferation. Meanwhile, the AMPK activator metformin significantly enhanced Eth-induced autophagy and inhibited proliferation. Computational docking and affinity assays showed that Eth directly interacted with the allosteric drug and metabolite site of AMPK to stabilize its activation. AMPK was less activated in tumor samples compared to normal breast tissues and was inversely associated with the prognosis of the patients. Moreover, Eth exhibited potent anti-BC activity in nude mice and favorable pharmacokinetics in rats. These characteristics render Eth as a promising candidate drug for further development and for designing new effective AMPK activators.

Keywords: AMP-activated protein kinase; autophagy; breast cancer; ethoxysanguinarine; molecular docking; pharmacokinetic.