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  • ROS are a series of

    2019-07-08

    ROS are a series of byproducts induced by oxidative stress, containing peroxides, superoxide, hydroxyl radical and singlet oxygen [6,7]. Recent accumulating evidence has demonstrated that a number of anticancer drugs, such as cisplatin, doxorubicin, and docetaxel, induce the apoptosis of cancer Acetylcysteine resulting from cellular ROS production [[8], [9], [10]]. Normally, cancer cells can tolerate oxidant stress by maintaining a balance between oxidant systems and antioxidant systems. Recent studies have demonstrated that the mechanism of ROS production by anticancer drugs is disruption of the redox balance by direct suppression of the antioxidant systems in cancer cells [11,12]. For example, glutathione (GSH) is a potent antioxidant that can eliminate cellular ROS via a redox reaction. Previous study has reported that upregulation of cellular GSH levels could make breast cancer cells resistant to the anticancer drug by overexpression of glutamate cysteine ligase, which is the key enzyme of GSH synthesis [13,14]. As discussed above, ROS-induced apoptosis and cell death through blocking GSH synthesis is a potential anticancer therapy for use against cancer cells. Recent studies suggest that STAT3, a transcription factor of the STAT family, plays pivotal roles in the majority of cancers, including lung, liver, bladder, prostate, gastric cancer and OS [[15], [16], [17]]. Constitutive activation of STAT3 has been implicated in tumor cell growth, proliferation, and anti-apoptosis. Under normal conditions, STAT3 resides in the cytoplasm as a monomer. Upon stimulation of protein tyrosine kinases (JAKs and Src) or cytokines (IL-6 and IL-10), STAT3 is activated through the phosphorylation of the tyrosine residue (Tyr705) and subsequent dimerization. Then, activated STAT3 translocates from the cytoplasm to the nucleus and then regulates the transcriptional activation of anti-apoptotic and cell-cycle regulating gene products, such as Bcl-2, XIAP, and cyclin D1. Considering its critical role in tumor growth and progression, STAT3 has become a promising target for antitumor treatment. Currently, several reports have reported that ROS can play pivotal roles in the activity of STAT3. STAT3 itself is susceptible to oxidation in cells under oxidative stress and was shown to be modified and repressed by cysteine glutathionylation [[18], [19], [20]]. Natural products derived from medicinal plants have been widely used as novel anticancer drugs because of their potent efficacy and safety. Many studies have reported that many anticancer drugs isolated from natural sources, such as alterol and toosendanin, significantly suppress tumor growth and progression by inhibiting STAT3 signaling cascades [21,22]. Glaucocalyxin A (GLA), which is isolated from Rabdosia japonica, has been found to exhibit a wide range of pharmacological efficacies, such as inhibition of platelet activating factor-induced platelet aggregation, immunosuppressive activity, and potent anticancer properties [[23], [24], [25], [26]]. The potent anticancer efficacy of GLA has been verified in multiple cancers, including liver, breast, blood and brain cancers [[27], [28], [29]]. These studies demonstrated that GLA exhibits antiproliferative and proapoptotic efficacies mainly mediated through inhibiting the c-jun N-terminal kinase (JNK) pathway, the serine/threonine kinase AKT pathway, or the mitochondria-mediated death pathway. In the present study, we specifically investigated whether GLA could suppress tumor growth and induce apoptosis of OS in vitro and in vivo. As expected, we determined that the mechanism of the anticancer effect exhibited by GLA is upregulating cellular ROS production by inhibiting GSH synthesis and then abrogating both the constitutive and inducible activation of STAT3, which is essential for the growth of OS.
    Materials and methods
    Results
    Discussion As the 5-year overall survival rate of OS is not optimistic, the discovery of novel molecular compounds is essential for the treatment of OS to improve prognosis. In this study, we detected GLA derived from Rabdosia japonica and showed for the first time that this compound exhibit a significant inhibitory effect on both constitutive and IL-6-inducible activation of STAT3 (Tyr705) and JAK2, the upstream regulator of STAT3, in OS. The aim of the following experiments is to elucidate the molecular mechanism of the anticancer effects of GLA in OS cells. First, it is exciting to note that GLA leads to an imbalance of the GSSG/GSH system by reducing the activity of cellular GR. This imbalance leads to significant cellular ROS production and potent oxidative stress. Second, we show that GLA significantly suppresses STAT3 activation and downregulates the expression of various STAT3-regulated genes, thereby inhibiting proliferation and growth in OS cells and xenograft tumors. Based on these findings, we ultimately elucidate the link between ROS-mediated oxidative stress and the inhibition of JAK2/STAT3 cascades caused by GLA in OS.