Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

Liu, Ting; Men, Qiuxu; Wu, Guixian; Yu, Chunrong; Huang, Zan; Liu, Xin; Li, Wenhua

doi:10.18632/oncotarget.3505

Cited by 47 publications

(34 citation statements)

References 47 publications

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“…It was demonstrated that tetrandrine induced autophagy in human hepatocellular carcinoma via mitochondrial dysfunction, ROS accumulation and activation of the extracellular signal-regulated kinase (ERK) signaling pathway (23). In addition, tetrandrine induced autophagy by triggering ROS generation and upregulating Notch1 signaling in acute premyelocytic leukemia cells (24). In contrast, tetrandrine was identified as a potent lysosomal deacidification agent to block autophagic flux in prostate cancer PC-3 and renal cell carcinoma 786-O cells (25).…”

Section: Discussionmentioning

confidence: 99%

Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells

Kou

Liu

et al. 2017

Oncology Reports

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Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra is a traditional Chinese medicine and exerts anticancer capacity in various types of cancers. Previous studies have shown that tetrandrine induces apoptosis in bladder cancer cells via activation of the caspase cascade. However, the underlying mechanism has not yet been reported. Autophagy is a cellular process involved in the degradation of broken proteins and aging organelles to maintain homeostasis. Recent studies indicate that autophagy is implicated in cancer therapy. Thus, we focused on the correlation between autophagy and apoptosis upon tetrandrine treatment in human bladder cancer cells. Firstly, our results observed a marked increase in autophagic double-membrane vacuoles and fluorescent puncta of red fluorescence protein-green fluorescence protein-LC3 (GRP-RFP-LC3) upon tetrandrine treatment, as evidenced by transmission electron microscopy and confocal fluorescence microscopy. Secondly, the expression of LC3-II was increased in tetrandrine-treated T24 and 5637 cells in a time- and concentration-dependent manner. Subsequently, downregulation of p62 and LC3 turnover assay further confirmed that tetrandrine induced autophagic flux in bladder cancer T24 and 5637 cells. Thirdly, the protein levels of phosphorylated-AMP-activated protein kinase (AMPK) and phosphorylated-acetyl-coenzyme A carboxylase (ACC) were upregulated in the tetrandrine-treated cells, while the mammalian target of rapamycin (mTOR)-related proteins were downregulated. Moreover, AICAR, a common AMPK activator, further increased the expression the LC3-II, while AMPK inhibitor compound C partially reversed the LC3-II protein levels in bladder cancer T24 cells. Finally, AICAR significantly reinforced the growth inhibition and apoptosis induction of tetrandrine in T24 and 5637 cells, while compound C had an opposite effect, suggesting that AMPK-mediated autophagy enhanced the cytotoxic and pro-apoptosis effect of tetrandrine in human bladder cancer cells. Taken together, the present study showed that tetrandrine induced autophagy in human bladder cancer cells by regulating the AMPK/mTOR signaling pathway, which contributed to the apoptosis induction by tetrandrine, indicating that tetrandrine may be a potential anticancer candidate for the treatment of bladder cancer, and autophagy may be a possible mechanism for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells

Kou

Liu

et al. 2017

Oncology Reports

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“…It would be helpful to prevent the development of hepatocellular carcinoma in the high-risk group of patients with chronic hepatitis or cirrhosis. Natural health products have attracted extensive attention in health promotion and disease treatment including cancer [2–4]. In addition, natural product-based drug discovery is a major route leading to developing therapeutic drugs for various diseases including cancer.…”

Section: Introductionmentioning

confidence: 99%

Ergosterol peroxide activates Foxo3-mediated cell death signaling by inhibiting AKT and c-Myc in human hepatocellular carcinoma cells

et al. 2016

Oncotarget

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Sterols are the important active ingredients of fungal secondary metabolites to induce death of tumor cells. In our previous study, we found that ergosterol peroxide (5α, 8α-epidioxiergosta-6, 22-dien-3β-ol), purified from Ganoderma lucidum, induced human cancer cell death. Since the amount of purified ergosterol peroxide is not sufficient to perform in vivo experiments or apply clinically, we developed an approach to synthesize ergosterol peroxide chemically. After confirming the production of ergosterol peroxide, we examined the biological functions of the synthetic ergosterol peroxide. The results showed that ergosterol peroxide induced cell death and inhibited cell migration, cell cycle progression, and colony growth of human hepatocellular carcinoma cells. We further examined the mechanism associated with this effect and found that treatment with ergosterol peroxide increased the expression of Foxo3 mRNA and protein in HepG2 cells. The upstream signal proteins pAKT and c-Myc, which can inhibit Foxo3 functions, were clearly decreased in HepG2 cells treated with ergosterol peroxide. The levels of Puma and Bax, pro-apoptotic proteins, were effectively enhanced. Our results suggest that ergosterol peroxide stimulated Foxo3 activity by inhibiting pAKT and c-Myc and activating pro-apoptotic protein Puma and Bax to induce cancer cell death.Oncotarget 33949

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“…The efficacy of tetrandrine on NB4 leukemia cells in vivo and in vitro revealed that tetrandrine-induced differentiation is accompanied by autophagy from the accumulation of ROS and by Notch1 signaling activation. Furthermore, autophagy and differentiation were also induced by tetrandrine in M5 type patient primary leukemia cells [71]. Different from an autophagy activator, Qiu et al presented tetrandrine as a potent lysosomal inhibitor, blocking autophagic flux at the lysosomal degradation stage in tumor cells, predominantly by neutralizing lysosomal acidity and then decreasing the recycling of cellular fuels [72].…”

Section: Inducing Cancer Cell Autophagymentioning

confidence: 99%

“…On the other hand, the tetrandirne-induced autophagy may play a protective function and weaken apoptosis in tumor cells which provide an efficient approach to synergize apoptosis by pharmacologically inhibiting autophagy [71, 74, 75]. …”

Section: Inducing Cancer Cell Autophagymentioning

confidence: 99%

Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy

Liu

2016

Oncotarget

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144

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Cancer is a disease caused by the abnormal proliferation and differentiation of cells governed by tumorigenic factors. Chemotherapy is one of the major cancer treatment strategies, and it functions by targeting the physiological capabilities of cancer cells, including sustained proliferation and angiogenesis, the evasion of programmed cell death, tissue invasion and metastasis. Remarkably, natural products have garnered increased attention in the chemotherapy drug discovery field because they are biologically friendly and have high therapeutic effects. Tetrandrine, isolated from the root of Stephania tetrandra S Moore, is a traditional Chinese clinical agent for silicosis, autoimmune disorders, inflammatory pulmonary diseases, cardiovascular diseases and hypertension. Recently, the novel anti-tumor effects of tetrandrine have been widely investigated. More impressive is that tetrandrine affects multiple biological activities of cancer cells, including the inhibition of proliferation, angiogenesis, migration, and invasion; the induction of apoptosis and autophagy; the reversal of multidrug resistance (MDR); and the enhancement of radiation sensitization. This review focuses on introducing the latest information about the anti-tumor effects of tetrandrine on various cancers and its underlying mechanism. Moreover, we discuss the nanoparticle delivery system being developed for tetrandrine and the anti-tumor effects of other bisbenzylisoquinoline alkaloid derivatives on cancer cells. All current evidence demonstrates that tetrandrine is a promising candidate as a cancer chemotherapeutic.

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Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells

Cited by 47 publications

References 47 publications

Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells

Autophagy induction enhances tetrandrine-induced apoptosis via the AMPK/mTOR pathway in human bladder cancer cells

Ergosterol peroxide activates Foxo3-mediated cell death signaling by inhibiting AKT and c-Myc in human hepatocellular carcinoma cells

Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy

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