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      Sinomenine inhibits the growth of melanoma by enhancement of autophagy via PI3K/AKT/mTOR inhibition

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          Melanoma is a common skin tumor in adults with high metastasis and mortality rates. Thus, finding a better effective approach to treat melanoma has become very urgent. Sinomenine (SIN), the major active compound of Sinomenium acutum, has shown antitumorigenic activities in certain cancers. However, its role in melanoma remains unclear.


          This study aimed to explore the effects of SIN on melanoma in vitro and in vivo, in addition to exploring the underlying mechanism.


          Mouse melanoma cell B16-F10 treated by SIN was analyzed by CCK8 assay and flow cytometry. Melanoma xenograft model was then established by subcutaneously injection with B16-F10 cells. Tumor growth was measured by immunohistochemistry. To further investigate the relative mechanism, the autophagy and PI3K/Akt/mTOR pathway were examined by immunofluorescence and Western blot.


          Our results revealed that SIN dose dependently inhibited the proliferation of B16-F10 cells in vitro and attenuated melanoma growth in vivo. In addition, SIN treatment promoted the apoptosis of B16-F10 cells in a dose-dependent manner, as demonstrated by the increase in apoptotic cells, Bax/Bcl-2 ratio, and caspase-3 activity. Moreover, preconditioning with SIN dramatically enhanced autophagy activity by increasing Beclin-1 and LC3II/LC3I expression, in addition to decreasing p62 expression and augmenting the number of LC3 puncta, in B16-F10 cells. More importantly, autophagy inhibitor chloroquine partly abolished SIN’s effects on cell growth and apoptosis. Furthermore, our results showed that SIN-triggered activation of autophagy was mediated by PI3K/Akt/mTOR signaling pathway.


          Our study has identified a novel function of SIN and provided a molecular basis for potential applications of SIN in the treatment of melanoma and other cancers.

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          Most cited references 31

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          Signal integration by mTORC1 coordinates nutrient input with biosynthetic output.

          Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, we discuss the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth. The emerging network of signalling pathways through which mTORC1 integrates systemic signals (secreted growth factors) with local signals (cellular nutrients - amino acids, glucose and oxygen - and energy, ATP) is detailed. Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology.
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            Is Open Access

            Metformin inhibits melanoma development through autophagy and apoptosis mechanisms

            Metformin is the most widely used antidiabetic drug because of its proven efficacy and limited secondary effects. Interestingly, recent studies have reported that metformin can block the growth of different tumor types. Here, we show that metformin exerts antiproliferative effects on melanoma cells, whereas normal human melanocytes are resistant to these metformin-induced effects. To better understand the basis of this antiproliferative effect of metformin in melanoma, we characterized the sequence of events underlying metformin action. We showed that 24 h metformin treatment induced a cell cycle arrest in G0/G1 phases, while after 72 h, melanoma cells underwent autophagy as demonstrated by electron microscopy, immunochemistry, and by quantification of the autolysosome-associated LC3 and Beclin1 proteins. In addition, 96 h post metformin treatment we observed robust apoptosis of melanoma cells. Interestingly, inhibition of autophagy by knocking down LC3 or ATG5 decreased the extent of apoptosis, and suppressed the antiproliferative effect of metformin on melanoma cells, suggesting that apoptosis is a consequence of autophagy. The relevance of these observations were confirmed in vivo, as we showed that metformin treatment impaired the melanoma tumor growth in mice, and induced autophagy and apoptosis markers. Taken together, our data suggest that metformin has an important impact on melanoma growth, and may therefore be beneficial in patients with melanoma.
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              β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation.

              Both PI3K/AKT/mTOR/S6K1 and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of β-caryophyllene oxide (CPO), a sesquiterpene isolated from essential oils of medicinal plants such as guava (Psidium guajava), oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) clove (Eugenia caryophyllata), and black pepper (Piper nigrum L.) on the PI3K/AKT/mTOR/S6K1 and MAPK activation pathways in human prostate and breast cancer cells. We found that CPO not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 signaling cascade; but also caused the activation of ERK, JNK, and p38 MAPK in tumor cells. CPO induced increased reactive oxygen species (ROS) generation from mitochondria, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and TUNEL staining, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, and cleavage of PARP. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented CPO-induced apoptosis. Subsequently, CPO also down-regulated the expression of various downstream gene products that mediate cell proliferation (cyclin D1), survival (bcl-2, bcl-xL, survivin, IAP-1, and IAP-2), metastasis (COX-2), angiogenesis (VEGF), and increased the expression of p53 and p21. Interestingly, we also observed that CPO can significantly potentiate the apoptotic effects of various pharmacological PI3K/AKT inhibitors when employed in combination in tumor cells. Overall, these findings suggest that CPO can interfere with multiple signaling cascades involved in tumorigenesis and used as a potential therapeutic candidate for both the prevention and treatment of cancer. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                06 August 2018
                : 12
                : 2413-2421
                [1 ]Department of Dermatology and Venereology, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China
                [2 ]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
                [3 ]Department of Cardiovasology, Beijing Chinese Medicine Hospital, Capital Medical University, Beijing, People’s Republic of China
                [4 ]Department of Plastic Surgery, Beijing Luhe Hospital, Capital Medical University, Beijing, People’s Republic of China, 3418139937@ 123456qq.com
                Author notes
                Correspondence: Xinhai Liu, Department of Plastic Surgery, Beijing Luhe Hospital, Capital Medical University, No 82, Xinhua South Road, Tongzhou District, Beijing 101149, People’s Republic of China, Tel +86 10 6954 3905, Email 3418139937@ 123456qq.com
                © 2018 Sun et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine

                sinomenine, melanoma, autophagy, pi3k/akt/mtor


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