Sophoridine exerts anti-arthritic effects on fibroblast-like synoviocytes and collagen-induced arthritis in rats.

The discovery of alternative medicines with fewer adverse effects is urgently needed for rheumatoid arthritis (RA). Sophoridine (SR), the naturally occurring quinolizidine alkaloid isolated from the leguminous sophora species, has been demonstrated to possess a wide range of pharmacological activities. However, the effect of SR on RA remains unknown. In this study, the collagen-induced arthritis (CIA) rat model and tumor necrosis factor alpha (TNFα)-induced fibroblast-like synoviocytes (FLSs) were utilized to investigate the inhibitory effect of SR on RA. The anti-arthritic effect of SR was evaluated using the CIA rat model in vivo and TNFα-stimulated FLSs in vitro. Mechanistically, potential therapeutic targets and pathways of SR in RA were analyzed through drug target databases and disease databases, and validation was carried out through immunofluorescence, immunohistochemistry, and Western blot. The in vivo results revealed that SR treatment effectively ameliorated synovial inflammation and bone erosion in rats with CIA. The in vitro studies showed that SR could significantly suppress the proliferation and migration in TNFα-induced arthritic FLSs. Mechanistically, SR treatment efficiently inhibited the activation of MAPKs (JNK and p38) and NF-κB pathways in TNFα-induced arthritic FLSs. These findings were further substantiated by Immunohistochemistry results in the CIA rat. SR exerts an anti-arthritic effect in CIA rats through inhibition of the pathogenic characteristic of arthritic FLSs via suppressing NF-κB and MAPKs (JNK and p38) signaling pathways. SR may have a great potential for development as a novel therapeutic agent for RA treatment.

QSAR prediction, synthesis, anticancer evaluation, and mechanistic investigations of novel sophoridine derivatives as topoisomerase I inhibitors.

Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.

Network pharmacology and in vitro experiments reveal sophoridine-induced apoptosis and G1 phase arrest via ROS-dependent PI3K/Akt/FoxO3a pathway activation in human bladder cancer cells.

Bladder cancer (BLCA), a common primary malignancy, exhibits resistance to conventional chemotherapeutic agents. Sophoridine (SR) is a quinoline alkaloid derived from the traditional Chinese herb Sophora alopecuroides L., which belongs to the legume family Sophoraceae. SR is reported to exert growth-inhibitory effects against several cancers. However, the mechanisms underlying the growth-inhibitory effects of SR on BLCA have not been elucidated. This study performed molecular and cellular experiments to verify the growth-inhibitory effects of SR on BLCA and the underlying mechanisms. SR inhibited cell proliferation and promoted apoptosis and G1-phase arrest through the PI3K/AKT/FoxO3a signaling pathway. More interestingly, the effects of SR can be attributed to the accumulation of reactive oxygen species (ROS) in vivo. ROS may be the upstream factor of this pathway. Additionally, SR inhibited the migration and invasion of BLCA cells in a concentration-dependent or time-dependent manner. This is the first study to demonstrate the ROS-dependent PI3K/AKT/FoxO3a pathway-mediated anticancer effect of SR and the anticancer mechanism of SR in BLCA. The correlation between SR-induced ROS-dependent cell proliferation inhibition, apoptosis, cell cycle arrest, and PI3K/AKT/FoxO3a suggests that SR is a promising novel therapeutic for BLCA.

Sophoridine Counteracts Obesity via Src-Mediated Inhibition of VEGFR Expression and PI3K/AKT Phosphorylation.

Sophoridine (SRP) is a natural quinolizidine alkaloid found in many traditional Chinese herbs, though its effect on adipose tissue is unclear. We improved serum lipid levels by administering SRP by gavage in high-fat diet (HFD)-fed C57BL/6 mice. After 11 weeks, SRP supplementation significantly reduced body weight gain and improved glucose homeostasis, while reducing subcutaneous fat and liver weight. SRP also inhibited cell proliferation and differentiation of 3T3-L1 cells. Proteomics analysis revealed that SRP inhibits adipocyte differentiation by interacting with Src, thereby suppressing vascular endothelial growth factor receptor 2 (VEGFR2) expression and PI3K/AKT phosphorylation. This study provides an empirical basis for the treatment of obesity with small molecules.

Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple-Negative Breast Cancer.

As a critical epigenetic modulator of gene expression, histone deacetylases (HDACs) have been involved in the pathogenesis and therapeutic investigation of cancer. Quinolizidine alkaloid sophoridine is known to have anticancer efficacy but with limited indication. By incorporating the pharmacophore of the HDAC inhibitor into the ring-opened sophoridine core, a new series of sophoridine hydroxamic acid derivatives were synthesized. After structure-activity studies, a selected compound was found to exert significant cytotoxicity in triple-negative breast cancer CAL-51 cells (IC50 1.17 µM), and demonstrated low nanomolar inhibitory potency toward HDAC1/3/6. Cellular functional assays indicated that this compound was able to induce apoptosis and cause accumulation of cells in the S phase of the cell cycle. Western blot analysis revealed it to decrease the expression of DNMT1, DNMT3a and DNMT3b by down-regulating phosphor-ERK1/2. Furthermore, treatment with this compound proved to block the PI3K/AKT/mTOR signaling in the PI3KCA and PTEN-mutant CAL-51 cells. Collectively, this work provides a novel lead compound for the development of potential therapeutics against triple-negative breast cancers, possibly mesenchymal-like subtype.

Research progress of sophoridine's pharmacological activities and its molecular mechanism: an updated review.

Background: Sophoridine, the major active constituent of Sophora alopecuroides and its roots, is a bioactive alkaloid with a wide range of pharmacological effects, including antitumor, anti-inflammatory, antiviral, antibacterial, analgesic, cardioprotective, and immunoprotective activities. Sophora flavescens Aiton is a traditional Chinese medicine that is bitter and cold. Additionally, it also exhibits the effects of clearing heat, eliminating dampness, and expelling insects. Aims of the study: To summarize the pharmacological research and associated mechanisms of sophoridine, we compiled this review by combining a huge body of relevant literature. Materials and methods: The information related to this article was systematically collected from the scientific literature databases including PubMed, Google Scholar, Web of Science, Science Direct, Springer, China National Knowledge Infrastructure, published books, PhD and MS dissertations. Results: Its antitumor activity is particularly remarkable, as it can inhibit cancer cell proliferation, invasion, and metastasis while inducing cell cycle arrest and apoptosis. Additionally, sophoridine also holds therapeutic potential for myocardial ischemia, osteoporosis, arrhythmias, and neurological disorders, primarily through the suppression of related inflammatory factors and cell apoptosis. However, sophoridine has also exhibited adverse effects such as hepatotoxicity and neurotoxicity. The antidisease effect and mechanism of sophoridine are diverse, so it has high research value. Conclusion: As an important traditional Chinese medicine alkaloid, modern pharmacological studies have demonstrated that sophoridine has prominent bioactivities, especially on anti-tumor anti-inflammation activities, and cardiovascular system protection. These activities provide prospects for novel drug development for cancer and some chronic diseases. Nevertheless, the understanding of the multitarget network pharmacology, long-term in vivo toxicity, and clinical efficacy of sophoridine require further detailed research.

Sophoridine alleviates hyperalgesia and anxiety-like behavior in an inflammatory pain mouse model induced by complete freund's adjuvant.

Chronic pain, along with comorbid psychiatric disorders, is a common problem worldwide. A growing number of studies have focused on non-opioid-based medicines, and billions of funds have been put into digging new analgesic mechanisms. Peripheral inflammation is one of the critical causes of chronic pain, and drugs with anti-inflammatory effects usually alleviate pain hypersensitivity. Sophoridine (SRI), one of the most abundant alkaloids in Chinese herbs, has been proved to exert antitumor, antivirus and anti-inflammation effects. Here, we evaluated the analgesic effect of SRI in an inflammatory pain mouse model induced by complete Freund's adjuvant (CFA) injection. SRI treatment significantly decreased pro-inflammatory factors release after LPS stimuli in microglia. Three days of SRI treatment relieved CFA-induced mechanical hypersensitivity and anxiety-like behavior, and recovered abnormal neuroplasticity in the anterior cingulate cortex of mice. Therefore, SRI may be a candidate compound for the treatment of chronic inflammatory pain and may serve as a structural basis for the development of new drugs.

Novel Sophoridine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, Acetylcholinesterase Inhibition, and Morphological Study.

Two series of novel sophoridine derivatives were designed, synthesized, and evaluated for their anti-mosquito activity. SOP-2g, SOP-2q, and SOP-2r exhibited potential larvicidal activity against Aedes albopictus larva with LC50 values of 330.98, 430.53, and 411.09 ppm, respectively. Analysis of structure-activity relationships indicated that the oxime ester group was beneficial for improving the larvicidal biological activity, whereas the long-chain aliphatic group and fused-ring group were introduced. Furthermore, the larvicidal mechanism was also investigated based on the inhibition assay of acetylcholinesterase (AChE) and the morphological observation of dead larva treated with derivatives. Results indicated that the AChE inhibitory activity of the preferred three derivatives were 63.16%, 46.67%, and 35.11%, respectively, at 250 ppm concentration. Additionally, morphological evidence demonstrated that SOP-2q and SOP-2r induced changes in the larva's intestinal cavity, caudal gill, and tail, thereby displaying larvicidal action against Ae. albopictus together with AChE inhibition. Therefore, this study implied that sophoridine and its novel derivatives could be used to control the population of mosquito larva, which may also be effective alkaloids to reduce the mosquito population density.

Sophoridine manifests as a leading compound for anti-arrhythmia with multiple ion-channel blocking effects.

BACKGROUND: Sophoridine (SR) has shown the potential to be an antiarrhythmic agent. However, SR's electrophysiological properties and druggability research are relatively inadequate, which limits the development of SR as an antiarrhythmic candidate. PURPOSE: To facilitate the development process of SR as an antiarrhythmic candidate, we performed integrated studies on the electrophysiological properties of SR in vitro and ex vivo to gain more comprehensive insights into the multi-ion channel blocking effects of SR, which provided the foundation for the further drugability studies in antiarrhythmic and safety studies. Firstly, SR's electrophysiological properties and antiarrhythmic potentials were recorded and assessed at the cell and tissue levels by comprehensively integrating the patch clamp with the Electrical and Optical Mapping systems. Subsequently, the antiarrhythmic effects of SR were validated by aconitine and ouabain-induced arrhythmia in vivo. Finally, the safety of SR as an antiarrhythmic candidate compound was evaluated based on the guidelines of the Comprehensive in Vitro Proarrhythmia Assay (CiPA). STUDY DESIGN: The antiarrhythmic effect of SR was evaluated at the in vitro, ex vivo, and in vivo levels. METHODS: Isolated primary cardiomyocytes and stable cell lines were prepared to explore the electrophysiologic properties of being a multiple ion-channel blocker in vitro by whole-cell patch clamp. Using electrical and optical mapping, the negative chronotropic effect of SR was determined in langendorff-perfused rat or guinea-pig hearts.The antiarrhythmic activity of SR was assessed by the ex vivo tachyarrhythmia models induced by left coronary artery ligation (LCAL) and isoproterenol (ISO). Canonical models of aconitine and ouabain-induced arrhythmia were used to verify the antiarrhythmic effects in vivo. Finally, the pro-arrhythmic risk of SR was detected in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hSCCMs) using a Microelectrode array (MEA). RESULTS: Single-cell patch assay validated the multiple ion-channel blockers of SR in transient outward current potassium currents (Ito), l-type calcium currents (ICa-l), and rapid activation delayed rectifier potassium currents (IKr). SR ex vivo depressed heart rates (HR) and ventricular conduction velocity (CV) and prolonged Q-T intervals in a concentration-dependent manner. Consistent with the changes in HRs, SR extended the active time of hearts and increased the action potential duration measured at 90% repolarization (APD90). SR could also significantly lengthen the onset time and curtail the duration of spontaneous ventricular tachycardia (VT) in the ex vivo arrhythmic model induced by LCAL. Meanwhile, SR could also significantly upregulate the programmed electrical stimulation (PES) frequency after the ISO challenge in forming electrical alternans and re-entrant excitation. Furthermore, SR exerted antiarrhythmic effects in the tachyarrhythmia models induced by aconitine and ouabain in vivo. Notably, the pro-arrhythmic risk of SR was shallow for a moderate inhibition of the human ether-à-go-go-related gene (hERG) channel. Moreover, SR prolonged field potential duration (FPDc) of hSCCMs in a concentration-dependent manner without early after depolarization (EAD) and arrhythmia occurrence. CONCLUSION: Our results indicated that SR manifested as a multiple ion-channel blocker in the electrophysiological properties and exerts antiarrhythmic effects ex vivo and in vivo. Meanwhile, due to the low pro-arrhythmic risk in the hERG inhibition assay and the induction of EAD, SR has great potential as a leading candidate in the treatment of ventricular tachyarrhythmia.

Research advance in antiviral effect of sophoridine / 中国药理学通报

Sophoridine is a quinolizidine alkaloid extracted from Sophora in legumes, which is one of the main active ingredients of Sophora alopecuroides L, Sophora flavescentis Ait and Sophora davidii (Franch.) skeels. Its molecular formula is C

Sophoridine Suppresses Herpes Simplex Virus Type 1 Infection by Blocking the Activation of Cellular PI3K/Akt and p38 MAPK Pathways.

Herpes simplex virus type 1 (HSV-1) is a ubiquitous and important human pathogen capable of causing significant clinical diseases ranging from skin damage to encephalitis, particularly in immunocompromised and neonatal hosts. Currently, widely used nucleoside analogs, including acyclovir and penciclovir, have some limitations in their use due to side effects and drug resistance. Herein, we report sophoridine's (SRI) dramatic inhibition of HSV-1 replication in vitro. SRI exhibited a remarkable inhibitory influence on HSV-1 virus-induced cytopathic effect and plaque formation, as well as on progeny viruses in Vero and HeLa cells, with selection indexes (SI) of 38.96 and 22.62, respectively. Moreover, SRI also considerably suppressed HSV-1 replication by hindering the expression of viral immediate-early (ICP0 and ICP22), early (ICP8 and TK), and late (gB and gD) genes and the expression of viral proteins ICP0, gB, and gD. We suggest that SRI can directly inactivate viral particles and block some stages in the life cycle of HSV-1 after adsorption. Further experiments showed that SRI downregulated the cellular PI3K/Akt signaling pathway and obstructed HSV-1 replication even more. Most importantly, SRI markedly repressed HSV-1-induced p38 MAPK pathway activation. Collectively, this natural bioactive alkaloid could be a promising therapeutic candidate against HSV-1 via the modulation of cellular PI3K/Akt and p38 MAPK pathways.

Sophoridine inhibits endotoxin-induced acute lung injury by enhancing autophagy of macrophage and reducing inflammation.

Acute lung injury (ALI) is characterized by uncontrolled inflammation, which can lead to respiratory distress syndrome and cause patient death. In this study, we sought to determine the role of sophoridine, a compound purified from sophora, in ALI. A mouse model of ALI was established by treating mice with LPS through nonexposed tracheal instillation. After LPS-induced mice were treated with sophoridine, LPS-induced alveolar wall thickening, alveolar interstitial inflammatory exudation and thickening, and the degree of pulmonary edema were found to be inhibited. Macrophages play an important role in inflammation, and in vitro experiments have demonstrated that sophoridine reduces the LPS-induced expression of inflammatory factors by macrophages, suggesting that sophoridine may inhibit lung inflammation in LPS-treated mice through reduces the secretion of inflammatory factors. Further, treatment with sophoridine up-regulated autophagy in macrophage cells in vitro and mouse lung tissues in vivo. LPS can bind to TLRs and activate the MyD88/NF-κB pathways, leading to increased inflammation in the pathogenesis of ALI. Our findings revealed that sophoridine down-regulated the expression of TLR4/MyD88/NF-κB and mTOR mRNA and protein in mouse pulmonary tissue. Collectively, these findings indicate that sophoridine may inhibit LPS-induced ALI by enhancing autophagy of macrophages and reducing inflammation.

Research Progress in the Pharmacological Activities, Toxicities, and Pharmacokinetics of Sophoridine and Its Derivatives.

Sophoridine is a natural quinolizidine alkaloid and a bioactive ingredient that can be isolated and identified from certain herbs, including Sophora flavescens Alt, Sophora alopecuroides L, and Sophora viciifolia Hance. In recent years, this quinolizidine alkaloid has gained widespread attention because of its unique structure and minimal side effects. Modern pharmacological investigations have uncovered sophoridine's multiple wide range biological activities, such as anti-cancer, anti-inflammatory, anti-viral, anti-arrhythmia, and analgesic functions, among others. These pharmacological activities and beneficial effects point to sophoridine as a strong potential therapeutic candidate for the treatment of various diseases, including several cancer types, hepatitis B virus, enterovirus 71, coxsackievirus B3, cerebral edema, cancer pain, heart failure, acute myocardial ischemia, arrhythmia, inflammation, acute lung injury, and osteoporosis. The data showed that sophoridine had adverse reactions, including hepatotoxicity and neurotoxicity. Additionally, analyses of sophoridine's safety, bioavailability, and pharmacokinetic parameters in animal models of research have been limited, especially in the clinic, as have been investigations on its structure-activity relationship. In this article, we comprehensively summarize the biological activities, toxicity, and pharmacokinetic characteristics of sophoridine and its derivatives, as currently reported in publications, as we attempt to provide an overall perspective on sophoridine analogs and the prospects of its application clinically.

Sophoridine: A review of its pharmacology, pharmacokinetics and toxicity.

BACKGROUND: Sophoridine is a bioactive alkaloid found in many Chinese herbs, such as Sophora alopecuroides l, Euchresta japonica Benth and Sophora moocrorftinan. Sophoridine hydrochloride injection has been approved as an anticancer drug in China. PURPOSE: This review aims to provide a comprehensive summary on the pharmacological, molecular mechanism, pharmacokinetic and toxicity studies of sophoridine. METHOD: PubMed, Web of Science and China National Knowledge Infrastructure were used for a systematic search with the keywords including "sophoridine", "pharmacology", "pharmacokinetics", and "toxicity". RESULTS: Emerging evidence suggests that sophoridine exhibits a broad spectrum of pharmacological activities including antitumor, anti-inflammatory, antiviral, myocardialprotective and hepatoprotective activities. These pharmacological properties lay foundation for using the plants containing sophoridine for the treatment of numerous diseases, such as cancer, colitis, injury of lungs, ischemia myocardial,etc. The mechanisms involved in the pharmacological actions of sophoridine are regulation of NF-κB, TLR4/IRF3, JNK/ERK, Akt/mTOR signaling pathways, down-regulating the expression of HMG3B, bcl-2, MMP-2, MMP-9, TNF-α, IL-1ß IL-6 and other cytokines or kinases. However, an increasing number of published reports indicated that sophoridine has serious adverse effects. The primary toxic effects are neurotoxicity and acute toxicity, which are of wide concern in worldwide. Moreover, sophoridine is reported to distribute in kidney, liver, uterus, lung and other organs. It undergoes glucuronidation and excreted in urine. CONCLUSION: Future studies should elucidate the detailed in vivo metabolism studies on sophoridine. The effect of substituent functional groups on sophoridine on metabolism, the enzymes involved in the metabolism and the chemistry of metabolites also should be studied. Either structural modification of sophoridine or its combined with other drugs may play a pivotal role to enhance its pharmacological activities and reduce its toxicity.

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple-Negative Breast Cancer through Inhibition of mTOR Signaling.

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.

Establishment of quantitative methodology for sophoridine analysis and determination of its pharmacokinetics and bioavailability in rat.

OBJECTIVE: The aim of this study is to develop a rapid and sensitive UPLC-MS/MS approach to determine the sophoridine (SOP) level in rat plasma and the pharmacokinetics of the substance. SIGNIFICANCE: Sophoridine is used as an anti-inflammatory, anti-virus, anti-microbial, and anti-tumor alkaloid. It is essential to explore specific detection methods for the quantitative analysis of SOP in the blood circulation. METHODS: The rat plasma samples were prepared by one-step protein precipitation with acetonitrile. Subsequently, the samples were separated by chromatography using a UPLC BEH C18 reversed-phase with an initial mobile phase of methanol and 0.1% formic acid aqueous solution. The gradient elution was performed at a fixed flow rate of 0.4 mL/min, and multiple reaction monitoring (MRM) mode with an electrospray positive ionization source was employed to detect the transitions of m/z 249.1 → 84.2 for SOP and m/z 264.3 → 69.8 for dendrobine (IS). The entire process required 3.5 min for each sample. RESULTS: A linear correlation was established over the range of 2-2000 ng/mL (r2≥0.9954) for SOP in rat plasma with a lower limit of quantification (LLOQ) at 2 ng/mL. The range of accuracy was tested between 94.90% and 100.80%, and the relative standard deviations (RSDs) toward both intra- and inter-day precision were <10%. Thus, this method was successfully applied to a pharmacokinetic study, and the subsequent results demonstrated a low absolute bioavailability of 2.32%. CONCLUSION: The present study established a reliable method that quantified the SOP concentration in rat plasma after administering a dose of 2 mg/kg intravenously or 20 mg/kg orally.

Biological effects and mechanisms of matrine and other constituents of Sophora flavescens in colorectal cancer.

The plant Sophora flavescens Ait. has been used in the clinical management of colorectal cancer (CRC). Its constituent compounds, notably the alkaloids matrine, oxymatrine, and sophoridine, have received considerable research attention in experimental models of CRC in vivo and in vitro. This review found that extracts of S. flavescens and/or its constituent compounds have been reported to inhibit CRC cell proliferation by inducing cell-cycle arrest at the G1 phase, inducing apoptosis via the intrinsic pathway, interfering in cancer metabolism, inhibiting metastasis and angiogenesis, regulating senescence and telomeres, regulating the tumour microenvironment and down-regulating cancer-related inflammation. In addition, matrine and oxymatrine reversed multi-drug resistance and enhanced the effects of chemotherapies. These anti-cancer effects were associated with regulation of several cellular signalling pathways including: MAPK/ERK, PI3K/AKT/mTOR, p38MAPK, NF-κB, Hippo/LATS2, TGF-ß/Smad, JAK/STAT3, RhoA/ROC, and Wnt/ ß-catenin pathways. These multiple actions in CRC suggest the alkaloids of S. flavescens may be therapeutic candidates for CRC management. Nevertheless, there remains considerable scope for future research into its flavonoid constituents, the effects of combinations of compounds, and the interaction between these compounds and anti-cancer drugs. In addition, more research is needed to investigate likely drug ligand-receptor interactions for each of the bioactive compounds.

Sophoridine Inhibits the Tumour Growth of Non-Small Lung Cancer by Inducing Macrophages M1 Polarisation via MAPK-Mediated Inflammatory Pathway.

Lung cancer is one of the most common and lethal neoplasms for which very few efficacious treatments are currently available. M1-like polarised tumour-associated macrophages (TAMs) are key mediators to modulate the tumour microenvironment, which play a key role in inhibiting cancer cell growth. Sophoridine, a naturally occurring alkaloid, exerts multiple pharmacological activities including anti-tumour and anti-inflammatory activities, but it has not been characterised as a regulator of tumour microenvironment towards NSCLC. Herein, the regulatory effects of sophoridine on the polarisation of THP-1 cells into TAMs and the anti-tumour effects of sophoridine-stimulated M1 polarised macrophages towards lung cancer cells were carefully investigated both in vitro and in vivo. The results showed that sophoridine could significantly promote M1 polarisation of RAW264.7 and THP-1-derived macrophages, leading to increased expression of pro-inflammatory cytokines and the M1 surface markers CD86 via activating MAPKs signaling pathway. Further investigations showed that sophoridine-stimulated RAW264.7 and THP-1-derived M1 macrophages effectively induced cell apoptosis as well as inhibited the cell colony formation and cell proliferation in both H460 and Lewis lung cancer cells. In Lewis-bearing mice model, sophoridine (15 or 25 mg/kg) significantly inhibited the tumour growth and up-regulated the expression of CD86/F4/80 in tumour tissues. Collectively, the findings clearly demonstrate that sophoridine promoted M1-like polarisation in vitro and in vivo, suggesting that sophoridine held a great therapeutic potential for treating lung cancer.

Sophoridine suppresses lenvatinib-resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression.

Hepatocellular carcinoma (HCC) is one of the most lethal cancer types with insufficient approved therapies, among which lenvatinib is a newly approved multi-targeted tyrosine kinase inhibitor for frontline advanced HCC treatment. However, resistance to lenvatinib has been reported in HCC treatment recently, which limits the clinical benefits of lenvatinib. This study aims to investigate the underlying mechanism of lenvatinib resistance and explore the potential drug to improve the treatment for lenvatinib-resistant (LR) HCC. Here, we developed two human LR HCC cell lines by culturing with long-term exposure to lenvatinib. Results showed that the vascular endothelial growth factor receptors (VEGFR)2 expression and its downstream RAS/MEK/ERK signalling were obviously up-regulated in LR HCC cells, whereas the expression of VEGFR1, VEGFR3, FGFR1-4 and PDGFRα/ß showed no difference. Furthermore, ETS-1 was identified to be responsible for VEGFR2 mediated lenvatinib resistance. The cell models were further used to explore the potential strategies for restoration of sensitivity of lenvatinib. Sophoridine, an alkaloid extraction, inhibited the proliferation, colony formation, cell migration and increased apoptosis of LR HCC cells. In vivo and in vitro results showed Sophoridine could further sensitize the therapeutic of lenvatinib against LR HCC. Mechanism studies revealed that Sophoridine decreased ETS-1 expression to down-regulate VEGFR2 expression along with downstream RAS/MEK/ERK axis in LR HCC cells. Hence, our study revealed that up-regulated VEGFR2 expression could be a predicator of the resistance of lenvatinib treatment against HCC and provided a potential candidate to restore the sensitivity of lenvatinib for HCC treatment.

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated ß-catenin degradation in gastric cancer.

BACKGROUND: As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. METHODS: The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. RESULTS: Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted ß-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3ß-independent) or altered GSK3ß activity, and thus exerted potent tumor-suppressive activities. CONCLUSION: Sophoridine depends on targeting ESRRG/ß-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.