Physcion, a naturally occurring anthraquinone derivative, induces apoptosis and autophagy in human nasopharyngeal carcinoma

Abstract

Aim: Physcion is a major bioactive ingredient in the traditional Chinese medicine Radix et Rhizoma Rhei, which has an anthraquinone chemical structure and exhibits a variety of pharmacological activities including laxative, hepatoprotective, anti-inflammatory, antimicrobial and anti-proliferative effects. In this study we investigated the effect of physcion on human nasopharyngeal carcinoma in vitro and in vivo, as well as the mechanisms underlying the anti-tumor action. Methods: The nasopharyngeal carcinoma cell line CNE2 was treated with physcion, and cell viability was detected using MTT and colony formation assays. Flow cytometry was used to assess the cell cycle arrest, mitochondrial membrane potential loss, apoptosis, autophagy and intracellular ROS generation. Apoptotic cell death was also confirmed by a TUNEL assay. The expression of target or marker molecules was determined using Western blotting. The activity of caspase-3, 8, and 9 was detected with an ELISA kit. A xenograft murine model was used to evaluate the in vivo anti-tumor action of physcion, the mice were administered physcion (10, 20 mg·kg -1 ·d -1 , ip) for 30 d.Results: Treatment with physcion (5, 10, and 20 μmol/L) dose-dependently suppressed the cell viability and colony formation in CNE2 cells. Physcion (10 and 20 μmol/L) dose-dependently blocked cell cycle progression at G 1 phase and induced both caspase-dependent apoptosis and autophagy in CNE2 cells. Furthermore, physcion treatment induced excessive ROS generation in CNE2 cells, and subsequently disrupted the miR-27a/ZBTB10 axis, resulting in repression of the transcription factor Sp1 that was involved in physcioninduced apoptosis and autophagy. Moreover, physcion-induced autophagy acted as a pro-apoptotic factor, and possibly contributed to physcion-induced apoptosis. In the xenograft murine model, administration of physcion dose-dependently suppressed the tumor growth without affecting the body weight. Furthermore, the anti-tumor effects of physcion were correlated with downregulation of Sp1 and suppression of miR-27a in the tumor tissues. Conclusion: Physcion induces apoptosis and autophagy in human nasopharyngeal carcinoma by targeting Sp1, which was mediated by ROS/miR-27a/ZBTB10 signaling. The results suggest that physcion is a promising candidate for the treatment of human nasopharyngeal carcinoma.

Retracted: Physcion Synergistically Enhances the Cytotoxicity of Sorafenib in Hepatocellular Carcinoma

“…Besides solid tumor, the role of physcion in hematological malignancies has also been established (Liu et al, ). Moreover, physcion‐induced autophagy has been shown to promote cell apoptosis in human nasopharyngeal carcinoma (Pang et al, ). In our previous work, we focused on the neoplastic activities of physcion against HCC and found that physcion could induce the intrinsic apoptotic pathway (Pan et al, ).…”

“…The apoptosis‐inducing effect of physcion in breast cancer cells, colon cancer cells, cervical carcinoma cells, and nasopharyngeal carcinoma cells has also been documented in a variety of studies (Chen et al, ; Hong et al, ; Pang et al, ; Wijesekara et al, ). Meanwhile, extracellular matrix metalloproteinase inducer (EMMPRIN) (Chen et al, ), 6‐phosphogluconate dehydrogenase (Lin et al, ), and Sp1 (Pang et al, ) have been considered to be molecule targets accounting for the antitumor activity of physcion. Our previous findings have also shown that physcion could inhibit tumor growth and induce apoptosis in HCC (Pan et al, , ).…”

“…The antineoplastic activity of physcion has been reported in colon cancer and leukemia cells (Ge et al, 2005). The apoptosisinducing effect of physcion in breast cancer cells, colon cancer cells, cervical carcinoma cells, and nasopharyngeal carcinoma cells has also been documented in a variety of studies (Chen et al, 2015b;Hong et al, 2014;Pang et al, 2016;Wijesekara et al, 2014). Meanwhile, extracellular matrix metalloproteinase inducer (EMMPRIN) (Chen et al, 2015b), 6-phosphogluconate dehydrogenase (Lin et al, 2015), and Sp1 (Pang et al, 2016) have been considered to be molecule targets accounting for the antitumor activity of physcion.…”

Effect of colony‐stimulating factor‐1 receptor overexpression on the growth of nasopharyngeal carcinoma xenografts in nude mice and its mechanism of action

“…Pang et al . believe that emodin methyl ether can induce the ROS/miR‐27a/ZBTB10 signaling axis by targeting Sp, and induce apoptosis and autophagy in nasopharyngeal carcinoma cells . Gao et al .…”

“…21 Pang et al believe that emodin methyl ether can induce the ROS/miR-27a/ZBTB10 signaling axis by targeting Sp, and induce apoptosis and autophagy in nasopharyngeal carcinoma cells. 22 Gao et al confirmed that overexpression of miR-138-5p enhances the sensitivity of nasopharyngeal carcinoma cells to radiation by targeting EIF4-EBP1. 23 Although the aforementioned studies have explored the relationship between autophagy and apoptosis in nasopharyngeal carcinoma on cancer cell proliferation, tumor growth, and radiotherapy reactivity, the conclusions are still not uniform.…”