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.
Highlights
Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide, with an estimated 2,088,849 cases and 626,679 deaths in 2018 (Bray et al, 2018)
Using an MTT assay, we found that Eth had moderate cytotoxicity to these cell lines, with IC50 values ranging from 2.63 mM to 9.15 mM (Figure 1C, Table 1)
We have demonstrated for the first time that Eth induces the activation of autophagy as a new direct AMPK activator, resulting in the inhibition of breast cancer (BC) proliferation in vitro and in vivo
Summary
Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide, with an estimated 2,088,849 cases and 626,679 deaths in 2018 (Bray et al, 2018). In China, BC is the leading cause of cancer death in women younger than 45 years. Based on reports in 2015 from the cancer statistics in China, 70.7 persons per 100,000 die annually. Ethoxysanguinarine Induces Autophagy from BC (Chen et al, 2016). The major treatment methods for BC patients are surgery, radiotherapy, and chemotherapy. Despite recent advances in diagnosis and treatment, BC mortality rates are still high, making newer and more advanced therapies indispensable. The development of novel agents for the prevention and treatment of human BC is highly desirable
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