Solamargine Research Articles

In vitro and in vivo antineoplastic activities of solamargine in colorectal cancer through the suppression of PI3K/AKT pathway.

Previous research has demonstrated the efficacy of SM in inhibiting tumor growth in various cancer types. The objective of this study was to examine the antineoplastic effects and molecular mechanisms of Solamargine (SM) in colorectal cancer. Colorectal cancer (CRC) cells were treated with different concentrations of SM to evaluate the anticancer concentration for further experimental measurements. Additionally, the antitumor efficacy of SM was assessed in a subcutaneously implanted tumor model of colorectal cancer. RNA-seq and bioinformatics analyses were employed to identify differentially expressed genes (DEGs) and elucidate the underlying molecular mechanisms in LoVo cells. Subsequently, the specific mechanism of SM-mediated anti-tumor activities was analyzed by protein expression methods. The results of in vitro assays demonstrated that SM exhibits significant inhibitory effects on cell proliferation, clone formation, and invasion, while also promoting apoptosis in SW48 and LoVo cells. In a mouse xenograft tumor model, intragastric administration of SM at doses of 5 or 10 mg/kg effectively suppressed tumor volume and weight, and induced cell apoptosis in vivo. SM treatment also down-regulated PCNA and Cyclin E protein expression, contributing to the regulation of apoptosis. Further analysis using RNA-seq, bioinformatics, and experimental measurements revealed that SM treatment upregulates PTEN expression, while significantly reducing the phosphorylation levels of Akt and mTOR in LoVo cells. Our study provides further evidence to support the notion that SM primarily induces apoptosis in colorectal cancer cells through the inhibition of the PI3K/Akt signaling pathway. Additionally, our investigation demonstrated the favorable safety profile of SM in a mouse model of colorectal cancer, thereby suggesting its potential as a promising therapeutic approach for the management of CRC.

Solamargine Induces Hepatocellular Carcinoma Cell Apoptosis and Ferroptosis via Regulating STAT1/MTCH1 Axis.

Solamargine (SM) has been shown to play anti-tumor role in hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of SM in HCC progression deserve further exploration. HCC cell proliferation and apoptosis were assessed by cell counting kit 8 assay, colony formation assay and flow cytometry. Ferroptosis was evaluated by detecting the levels of Fe2+, iron, MDA, ROS and GSH in HCC cells. In addition, mitochondrial carrier 1 (MTCH1) mRNA level was detected by quantitative real-time PCR. Western blot was used to test MTCH1 and signal transduction and activation of transcription 1 (STAT1) protein levels. Dual-luciferase reporter assay was employed to analyze the interaction between STAT1 and MTCH1. A mouse xenograft model was also constructed to explore the role of SM in vivo. SM could potentially suppress HCC cell growth by inducing ferroptosis. MTCH1 was highly expressed in HCC tissues and cells, and its silencing inhibited HCC cell proliferation, promoted apoptosis and ferroptosis. MTCH1 expression was reduced by SM, and its overexpression reversed SM-induced HCC cell apoptosis and ferroptosis. Furthermore, STAT1 facilitated MTCH1 transcription and promoted its expression. Besides, STAT1 expression could be reduced by SM, and its overexpression abolished the decreasing effect of SM on MTCH1 expression. In vivo, SM suppressed HCC tumor growth by reducing MTCH1 expression. SM promoted HCC cell apoptosis and ferroptosis via the STAT1/MTCH1 axis.

Screening of alkaloids and withanolides isolated from Solanaceae plants for antifungal properties against non-wild type Sporothrix brasiliensis

Antifungal resistance has often been found in animal sporotrichosis in Southern Brazil. The biological potential of compounds from plants of the Solanaceae family against infectious diseases is known, however, it is still unknown against Sporothrix brasiliensis. This study evaluated the anti-Sporothrix brasiliensis activity, synergism, cytotoxicity, and action mechanism of steroidal lactones (withanolides) and alkaloids isolated from these plants. Pure compounds of withanolide D (WNOD), physalin F (PHYF), withanicandin (WNIC), nicandin B (NICB), solasonine (SSON), and solamargine (SMAR) were tested against 12 Sporothrix brasiliensis isolated from cats (n = 11) and dogs (n = 2) through M38-A2 CLSI. For the compounds with the best activity, a checkerboard assay for synergism, sorbitol protection, and ergosterol effect for action mechanism; and MTT test for cytotoxicity were performed. The withanolides WNOD, PHYF, WNIC, and NICB were not antifungal, but SSON (MIC 0.125–1 mg/mL) and SMAR (MIC 0.5–1 mg/mL) were both fungistatic and fungicidal (MFC 0.5–1 mg/mL for both) against wild-type (WT) and non-WT isolates. The activity of SSON and SMAR was indifferent when combined with itraconazole. In the mechanism of action, cell wall and plasma membrane by complexation with ergosterol seemed to be two target structures of SSON and SMAR. SSON was selected for cytotoxicity, whose cell viability in MDBK cells ranged from 28.85 % to 101.75 %, and was higher than 87.49 % at concentrations ≤0.0015 mg/ml. Only the steroidal alkaloids SSON and SMAR were active against non-WT isolates, being promising antifungal candidates for the treatment of feline and canine sporotrichosis with low susceptibility to itraconazole.

Solamargine induces apoptosis of human renal carcinoma cells via downregulating phosphorylated STAT3 expression.

Solamargine (SM), an active compound derived from Solanum nigrum, triggers apoptosis and inhibits the metastatic and oxidative activities of various types of tumor cells. However, the effect of SM on human renal carcinoma cells remains unknown. In the present study, the molecular mechanisms underlying the antitumor effects of SM on ACHN and 786-O cells were elucidated. Specifically, MTT and colony formation assays were conducted to evaluate the impact of SM treatment on the proliferation of ACHN and 786-O cells, and flow cytometry was conducted to determine the influence of SM on the apoptosis rates of these cells. In addition, the expression of target proteins was determined by western blotting. The results revealed that SM not only inhibited cell viability but also promoted the apoptosis of ACHN and 786-O cells in a time- and dose-dependent manner. Moreover, treatment of ACHN and 786-O cells with SM significantly enhanced the caspase-3, caspase-8 and caspase-9 activities. Furthermore, SM downregulated the expression of phosphorylated signal transducer and activator of transcription-3 (p-STAT3) and Bcl-2 but increased the expression of cleaved caspase-3, -8, -9 and Bax. BAY2353, a p-STAT3 inhibitor, inhibited the viability of ACHN and 786-O cells, increased the expression of cleaved caspase-9 and Bax and decreased the expression of p-STAT3 and Bcl-2. Further experiments demonstrated that SM inhibited tumor growth in xenograft nude mice without causing specific toxicity to the major organs. Collectively, these findings indicated that SM not only inhibited the viability but also promoted the apoptosis of ACHN and 786-O cells, through a mechanism involving downregulation of p-STAT3 expression.

Solamargine enhanced gefitinib antitumor effect via regulating MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) showed great therapeutic efficacy for non-small cell lung cancer (NSCLC) patients. However, acquired resistance severely limits the clinical application and efficacy of EGFR-TKIs. In the current study, we found that solamargine (SM), a natural alkaloid derived from the fruit of Lycium tomato lobelia, has been found to inhibit the progression of NSCLC and enhance the anticancer effect of EGFR-TKIs. In brief, SM significantly inhibited the cell viability of NSCLC cells and enhanced the anticancer effect of gefitinib (GFTN) and erlotinib (ERL). Mechanistically, SM decreased the expression of MALAT1 and induced miR-141-3p, whereas reduced SP1 protein levels. Interestingly, both MALAT1 and Sp1 have classical and conservative binding sites of miR-141-3p in their 3'-UTR regions. Silence of MALAT1 and overexpression of miR-141-3p both decreased the protein expression of Sp1. Subsequently, promoter activity and protein expression of IGFBP1 were upregulated by SM, which was not observed in cells with SP1 overexpression. Moreover, the inhibitory effect of SM on cell growth was significantly blocked by knockdown of IGFBP1 expression. More importantly, the combination of SM and GFTN synergistically inhibited the progression of lung cancer. Similar results were observed in experiments in vivo. Finally, the clinical relevance of MALAT1, Sp1 and IGFBP1 was further validated using bioinformatics analysis. Taken together, we confirmed that SM significantly enhanced the anticancer effect of EGFR-TKIs by regulating the MALAT1/miR-141-3p/Sp1/IGFBP1 signaling pathway. This study unravels a novel mechanism and suggests a new potential NSCLC-associated therapy.

Anticancer activity of glycoalkaloids from Solanum plants: A review.

Cancer is still one of the main causes of death worldwide. For this reason, new compounds that have chemotherapeutic potential have been identified. One such group of substances is Solanaceae glycoalkaloids (GAs). They are natural compounds produced by plants widely used in traditional medicine for healing many disorders. Among others, GAs exhibit significant antitumor properties, for example, a strong inhibitory effect on cancer cell growth. This activity can result in the induction of tumor cell apoptosis, which can occur via different molecular pathways. The molecular mechanisms of the action of GAs are the subject of intensive research, as improved understanding could lead to the development of new cancer therapies. The genetic basis for the formation of neoplasms are mutations in protooncogenes, suppressors, and apoptosis-controlling and repair genes; therefore, substances with antineoplastic properties may affect the levels of their expression or the levels of their expression products. Therapeutic compounds can be applied separately or in combination with other drugs to increase the efficiency of cancer therapy; they can act on the cell through various mechanisms at different stages of carcinogenesis, inducing the process of apoptosis, blocking cell proliferation and migration, and inhibiting angiogenesis. This review summarizes the newest studies on the anticancer properties of solanine (SN), chaconine (CH), solasonine (SS), solamargine (SM), tomatine (TT) and their extracts from Solanum plants.

Solamargine Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma by Decreasing LncRNA HOXA11-As Expression.

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the high mortality cancers with a poor prognosis, which is driving the development of new chemotherapeutic agents. We identified the anticancer effects of a natural compound, solamargine (SM), on FaDU cells and explored its mechanism in terms of non-coding RNA. It was observed that SM inhibited the proliferation of FaDU cells with an IC50 of 5.17 μM. High-throughput sequencing data revealed that lncRNA HOXA11-AS was significantly downregulated in cells co-incubated with SM. Further assays demonstrated that SM-induced downregulation of lncRNA HOXA11-AS showed important implications for apoptosis. Given the properties of HOXA11-AS as a miR-155 sponge, we further confirmed that SM upregulated the expression of miR-155 in FaDU cells. C-Myc is a transcription factor that regulates cell differentiation and apoptosis, whose mRNA is considered to be targeted by miR-155. We showed that c-Myc expression was downregulated by SM and accompanied by increased apoptosis, which was consistent with the findings of transcriptome sequencing. Furthermore, SM administration suppressed xenograft tumor growth in a xenograft mouse model in vivo. In the light of the aforementioned findings, our results suggested that SM downregulated the expression of HOXA11-AS, which in turn induces apoptosis by downregulating c-Myc in FaDU, providing evidence for the anticancer effect of SM on HSCC and uncovering the effect of SM on non-coding RNAs as, at least partly, a mechanism of action.

Solamargine Alleviated UVB-Induced Inflammation and Melanogenesis in Human Keratinocytes and Melanocytes via the p38 MAPK Signaling Pathway, a Promising Agent for Post-inflammatory Hyperpigmentation.

Post-inflammatory hyperpigmentation (PIH) is a common acquired pigmentary disorder occurring after skin inflammation or injury. Ultraviolet B irradiation could exaggerate PIH clinically due to its effect on promoting cutaneous inflammation and melanogenesis in keratinocytes and melanocytes, respectively. Solamargine (SM), a steroidal alkaloid glycoside extracted from Solanum undatum, significantly inhibits Ultraviolet B (UVB)-induced pro-inflammatory cytokines IL-1α, IL-1β, IL-8, and IFN-γ, as well as paracrine melanogenic factors ET-1, α-MSH, and bFGF in human keratinocytes. Additionally, SM significantly attenuated UVB-induced melanin synthesis in human epidermal melanocytes through down-regulation of tyrosinase activity and expression of MITF, TRP-1, TRP-2, and tyrosinase. SM exerted an anti-inflammatory effect in UVB-irradiated keratinocytes through the p38 MAPK/Nrf2/HO-1 signaling pathway. With its anti-inflammatory and whitening effect, SM may improve PIH through paracrine regulations of keratinocytes and direct action on melanocytes, making it a promising agent for PIH.

Solamargine induces autophagy-mediated apoptosis and enhances bortezomib activity in multiple myeloma.

Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent‐induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti‐MM activity. In particular, SM suppressed the viability of MM cell lines (ARP‐1 and NCI‐H929) in a concentration‐ and time‐dependent manner, inducing apoptosis in these cells. RNA‐seq analysis showed that treatment with SM led to the upregulation of genes associated with cell death and autophagy in H929 cells. Further, we found that treatment with SM activated autophagy in the MM cells, as incubation with 3‐Methyladenine, an inhibitor of autophagy, significantly alleviated SM‐triggered apoptosis and inhibition of viability in MM cells. Interestingly, we also observed a synergistic effect between SM and bortezomib (BTZ), a common chemotherapeutic agent for MM, in both MM cells and human bone marrow CD138+ primary myeloma cells. We also confirmed the single‐agent efficacy of SM and the synergistic effects between SM and BTZ in an MM xenograft mouse model. Collectively, these findings indicate that SM exerts an anti‐MM effect, at least in part, by activating cell autophagy and reveal that SM alone or in combination with BTZ is a potential therapeutic strategy for treating MM.

Solamargine inhibits the growth of hepatocellular carcinoma and enhances the anticancer effect of sorafenib by regulating HOTTIP-TUG1/miR-4726-5p/MUC1 pathway.

Hepatocellular carcinoma (HCC) is one of the most common primary malignancies. Drug resistance has significantly prevented the clinical application of sorafenib (SF), a first‐line targeted medicine for the treatment of HCC. Solamargine (SM), a natural alkaloid, has shown potential antitumor activity, but studies about antitumor effect of SM are obviously insufficient in HCC. In the present study, we found that SM significantly inhibited the growth of HCC and enhanced the anticancer effect of SF. In brief, SM significantly inhibited the growth of HepG2 and Huh‐7 cells. The combination of SM and SF showed a synergistic antitumor effect. Mechanistically, SM downregulated the expression of long noncoding RNA HOTTIP and TUG1, followed by increasing the expression of miR‐4726‐5p. Moreover, miR‐4726‐5p directly bound to the 3′‐UTR region of MUC1 and decreased the expression of MUC1 protein. Overexpression of MUC1 partially reversed the inhibitory effect of SM on HepG2 and Huh‐7 cells viability, which suggested that MUC1 may be the key target in SM‐induced growth inhibition of HCC. More importantly, the combination of SM and SF synergistically restrained the expression of MUC1 protein. Taken together, our study revealed that SM inhibited the growth of HCC and enhanced the anticancer effect of SF through HOTTIP‐TUG1/miR‐4726‐5p/MUC1 signaling pathway. These findings will provide potential therapeutic targets and strategies for the treatment of HCC.

A Programmed Cell-Mimicking Nanoparticle Driven by Potato Alkaloid for Targeted Cancer Chemoimmunotherapy.

Membrane camouflaged-nanoparticles (CM-NPs) have been exploited to inherit desired functionalities from source cells. Despite those advantages, membrane cloak may play a "double-edged sword" role in tumor-targeting therapy, as the intact membrane coating may hinder function-exertion of loaded drugs after reaching predetermined site. Therefore, further optimization of CM-NPs is still needed to enhance their delivery efficiency. Herein, natural product, Solamargine (SM), a cholesterol-affiliative amphiphilic potato alkaloid is first applied as core component of "inner core," to design a cell-mimicking "core-shell" nanoparticle (RBC-SLip) with acid-responsive off-coating properties for tumor-targeted therapy. Owing to red blood cell membrane (RBCm)-derived outer coating, it circulates stably in physiological conditions. While it would undergo an off-coating morphological change in response to acid stimuli in tumor microenvironment (TME), afterwards, the resulting off-coating liposome (SLip) shows active tumor-targeting and endosomal escape abilities, thus contributing to superior antitumor efficacy. In addition, SM also possesses natural TME-modulating ability; therefore, RBC-SLip can synergize with the PD1/PD-L1 blockade immunotherapy when encapsulated with PTX to achieve enhanced chemoimmunotherapy. The off-coating strategy developed by natural products SM, provide a brand-new perspective to optimize CM-NPs, and it also embodies application value of "unification of medicines and excipients" of natural products.

Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays

Solanum lycocarpum fruits contain two major glycoalkaloids (GAs), solamargine (SM) and solasonine (SS). These compounds are reported as cytotoxic. However, they have poor water solubility and low bioavailability. To overcome these disadvantages and getting an efficient formulation the current study aimed to develop, characterize, and test the effectiveness of a nanotechnology-based strategy using poly(D,L-lactide) (PLA) nanoparticles functionalized with folate as delivery system of glycoalkaloidic extract (AE) for bladder cancer therapy. The strategic of adding folic acid into nanoformulations can increase the selectivity of the compounds to the cancer cells reducing the side effects. Our results revealed the successful preparation of AE-loaded folate-targeted nanoparticles (NP-F-AE) with particle size around 177 nm, negative zeta potential, polydispersity index <0.20, and higher efficiency of encapsulation for both GAs present in the extract (>85 %). To investigate the cellular uptake, the fluorescent dye coumarin-6 was encapsulated into the nanoparticle (NP-F-C6). The cell studies showed high uptake of nanoparticles by breast (MDA-MB-231) and bladder (RT4) cancer cells, but not for normal keratinocytes cells (HaCaT) indicating the target uptake to cancer cells. The cytotoxicity of nanoparticles was evaluated on RT4 2D culture model showing 2.16-fold lower IC50 than the free AE. Furthermore, the IC50 increased on the RT4 spheroids compared to 2D model. The nanoparticles penetrated homogeneously into the urotheliumof porcine bladder. These results showed that folate-conjugated polymeric nanoparticles are potential carriers for targeted glycoalkaloidic extract delivery to bladder cancer cells.

The regulation and interaction of colon cancer-associated transcript-1 and miR7-5p contribute to the inhibition of SP1 expression by solamargine in human nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy with higher incidence in Southern China and Southeast Asia. Solamargine (SM), a steroidal alkaloid glycoside, has been shown to have anticancer properties. However, the underlying mechanism involved remains undetermined. In this study, we showed that SM inhibited the growth of NPC cells. Mechanistically, we found that solamargine decreased lncRNA colon cancer‐associated transcript‐1 (CCAT1) and increased miR7‐5p expression. There was a reciprocal interaction of CCAT1 and miR7‐5p. In addition, SM inhibited the expression of SP1 protein and promoter activity, which was strengthened by miR7‐5p mimics and inhibited by overexpressed CCAT1. MiR7‐5p could bind to 3'‐UTR of SP1 and attenuated SP1 gene expression. Exogenously expressed SP1 feedback resisted SM‐increased miR7‐5p expression and more importantly reversed SM‐inhibited growth of NPC cells. Finally, SM inhibited NPC tumor growth in vivo. Collectively, our results show that SM inhibits the growth of NPC cells through reciprocal regulation of CCAT1 and miR7‐5p, followed by inhibition of SP1 gene expression in vitro and in vivo. The interregulation and correlation among CCAT1, miR7‐5p and SP1, and the feedback regulatory loop unveil the novel molecular mechanism underlying the overall responses of SM in anti‐NPC.

Novel reciprocal interaction of lncRNA HOTAIR and miR‐214‐3p contribute to the solamargine‐inhibited PDPK1 gene expression in human lung cancer

Solamargine (SM) has been shown to have anti‐cancer properties. However, the underlying mechanism involved remains undetermined. We showed that SM inhibited the growth of non‐small cell lung cancer (NSCLC) cells, which was enhanced in cells with silencing of long non‐coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), while it overcame by overexpression of HOTAIR. In addition, SM increased the expression of miR‐214‐3p and inhibited 3‐phosphoinositide‐dependent protein kinase‐1 (PDPK1) gene expression, which was strengthened by miR‐214‐3p mimics. Intriguingly, HOTAIR could directly bind to miR‐214‐3p and sequestered miR‐214‐3p from the target gene PDPK1. Intriguingly, overexpression of PDPK1 overcame the effects of SM on miR‐214‐3p expressions and neutralized the SM‐inhibited cell growth. Similar results were observed in vivo. In summary, our results showed that SM‐inhibited NSCLC cell growth through the reciprocal interaction between HOTAIR and miR‐214‐3p, which ultimately suppressed PDPK1 gene expression. HOTAIR effectively acted as a competing endogenous RNA (ceRNA) to stimulate the expression of target gene PDPK1. These complex interactions and feedback mechanisms contribute to the overall effect of SM. This unveils a novel molecular mechanism underlying the anti‐cancer effect of SM in human lung cancer.

Solamargine inhibits proliferation and promotes apoptosis of CM-319 human chordoma cells through suppression of notch pathway

Background: Solamargine (SM), which represents a natural steroid alkaloid glycoside compound and a cytotoxic agent, has been proved to enhance the sensitivity of lung cancer cells to tumor necrosis factors (TNFs). In this study, we aimed to investigate the roles and mechanisms of SM in chordoma. Methods: Cell viability, proliferation, apoptosis and cell cycle were measured by cell counting Kit-8 (CCK-8) assay, 5(6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling and flow cytometry (FCM), respectively. Western blot and quantitative real-time reverse transcription PCR (qRT-PCR) assays were performed to detect the expressions of related mRNAs and proteins. Results: The results revealed that SM distinctly suppressed the proliferation of CM-319 cells. SM significantly induced the CM-319 cells apoptosis through up-regulating the expression levels of Caspase-3/8/9. The cell cycle of CM-319 cells was blocked by SM in G1 phase. Moreover, SM could significantly suppress the Notch pathway in CM-319 cells. Conclusions: In conclusion, SM suppressed the proliferation and enhanced the apoptosis ability of CM-319 cells via suppressing the Notch pathway. The results suggested that SM might be a novel therapeutic agent and supported the utilization of SM in chordoma.

Reciprocal Interaction of lncRNA HOTAIR and miR-214-3p Contribute to the Solamargine-Inhibited PDPK1 Gene Expression in Human Lung Cancer Cells

Background: Solamargine (SM), a natural plant based photochemical has been shown to have anti-cancer properties. However, the underlying mechanism of this effect remains to be determined. Methods: Cell viability and growth were measured via MTT and Cell-Light EdU assays. The expressions of HOTAIR, miR-214-3p andPDPK1 were examined via qRT-PCR and Western blot, respectively. The promoter activity of HOTAIR and PDPK1 were determined using Secrete-Pair Dual Luminescence Assay. Luciferase reporter assays and RNA immunoprecipitation determined the interactions among miR-214-3p, HOTAIR and PDPK1. Exogenous expressions of HOTAIR and PDPK1 were carried out by transient transfection assays. A mouse xenograft tumor model was used to further evaluate the effects of SM in vivo. Findings: SM inhibited the growth of non-small cell lung cancer (NSCLC) cells, which was not observed in cells stably transfected with PDPK1. While silencing of HOTAIR reduced cell growth, over-expression of HOTAIR resisted the SM mediated inhibition of cell growth. SM increased the expression of miR-214-3p and there was a reciprocal interaction between the HOTAIR and miR-214-3p. Furthermore, SM inhibited PDPK1 gene expression and the physical binding of miR-214-3p to PDPK1 3-UTR. MiR-214-3p mimics inhibited PDPK1 expression. Intriguingly, HOTAIR could directly bind to miR-124-3p and sequestered miR-214-3p from the target gene PDPK1. Finally, in a feedback mechanism, over-expression of PDPK1 reduced the HOTAIR and miR-214-3p expressions, and neutralized the SM-inhibited cell growth. Similar results were observed in vivo. Interpretation: SM inhibited NSCLC cell growth through the reciprocal interaction between HOTAIR and miR-214-3p, which ultimately suppressed PDPK1 gene expression. This unveils a novel molecular mechanism underlying the anti-cancer effect of SM in human lung cancer. Funding Statement: This work was supported in part by the grants from the National Nature Scientific Foundation of China (Nos. 81403216, 81673845, 81703551 and 81871863), the Science and Technology Program of Guangzhou (No. 201607010385), the Major Program of National Natural Science Foundation of Guangdong (No. 2018B030311061), the Discipline of Integrated Chinese and Western Medicine in Guangzhou University of Chinese Medicine (No. A1-Af-D018161Z1513), the Special Science and Technology Join fund from Guangdong Provincial Department of Science and Technology-Guangdong Academy of Traditional Chinese Medicine (No. 2014A020221024). The funders did not play a role in manuscript design, data collection, data analysis, interpretation nor writing of the manuscript. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: Animal studies were performed according to the protocols approved by the Institutional Animal Care and Use Committee of Guangdong Provincial Hospital of Chinese Medicine (Ethics Approval Number 2017037) and the National Institutes of Health guidelines for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978).

Fe3O4-solamargine induces apoptosis and inhibits metastasis of pancreatic cancer cells.

Fe3O4-magnetic liposome (MLP) can deliver drugs to target tissues and can increase drug efficacy. The present study aimed to investigate the effects of solamargine (SM) and Fe3O4-SM in pancreatic cancer (PC). Cell viability was detected using a Cell Counting kit-8 assay. Apoptosis and cell cycle progression was tested using a flow cytometry assay. A scratch assay was used to examine cell metastasis. Quantitative polymerase chain reaction, western blot analysis or immunohistochemical analysis were performed to determine the expression of target factors. Magnetic resonance imagining (MRI) and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling were conducted to detect tumor growth and apoptosis in vivo, respectively. It was demonstrated that Fe3O4-SM inhibited cancer cell growth via a slow release of SM over an extended period of time. SM was revealed to induce apoptosis and cell cycle arrest. Furthermore, SM decreased the expression of X-linked inhibitor of apoptosis, Survivin, Ki-67, proliferating cell nuclear antigen and cyclin D1, but increased the activity of caspase-3. It was also observed that SM inhibited tumor cell metastasis by modulating the expression of matrix metalloproteinase (MMP)-2 and TIMP metallopeptidase inhibitor-2. Furthermore, the phosphorylation of protein kinase B and mechanistic target of rapamycin was suppressed by SM. Notably, the effect of SM was enhanced by Fe3O4-SM. The malignant growth of PC was decreased by SM in vivo. Furthermore, the expression of Ki-67 was decreased by SM and Fe3O4-SM. Additionally, cell apoptosis was increased in the Fe3O4-SM group, compared with the SM group. The present study illustrated the antitumor effect and action mec hanism produced by SM. Additionally, it was demonstrated that Fe3O4-SM was more effective than SM in protecting against PC.

IN VITRO Anticancer Activity and Physicochemical Properties of SOLANUM LYCOCARPUM Alkaloidic Extract Loaded in Natural Lipid-Based Nanoparticles

Bladder cancer (BC) is the 9th most common cancer in the worldwide. BC's treatment is still a challenging goal. Thereby, the screening of natural compounds as solasonine (SS) and solamargine (SM) that exhibit antitumor activity is interesting to BC therapy. This work aimed to develop natural lipid-based nanoparticles (NLN) as carrier system of S. lycocarpum's fruits alkaloidic extract (AE), rich in SS and SM, and to evaluate its antitumor activity in bladder cancer cells. The NLN-AE exhibited 56 nm of diameter, low polydispersity index with shelf life estimated of 12 months, measured by LUMiSizer®. NLN-AE showed low recrystallization index with high encapsulation efficiency of SS (86%) and SM (89%). A sustained release profile was verified after 36 h. The free AE exhibited antitumor activity in bladder cancer cells. The cell viability decreased 5.4 fold when AE was encapsulated in NLN. Thus, NLN-AE has higher anti-proliferative activity than the free AE.

Solamargine inhibits the migration and invasion of HepG2 cells by blocking epithelial-to-mesenchymal transition.

Solamargine (SM), a steroidal alkaloid glycoside purified from the Chinese traditional herb Solanum incanum, is known to possess various biological activities. However, only a few previous studies have reported the anti-metastatic activity of SM. In the present study, the inhibitory effects of SM on metastatic action were investigated in human HepG2 cells. The proliferation effects of SM on the HepG2 cells was evaluated by MTT and colony formation assays. Wound-healing and Transwell assays were performed to examine the migration and invasion effects on SM-treated HepG2 cells. The epithelial-to-mesenchymal transition (EMT)-associated markers (E-cadherin, Vimentin and N-cadherin) were detected by western blotting analysis. In the present study, MTT and colony formation assays indicated that SM suppressed HepG2 cell viability in a dose-dependent manner. The wound-healing and Transwell assays revealed that the migration and invasion activities were significantly inhibited following exposure to SM. EMT has been demonstrated to be essential for promoting migration and invasion in tumor cells and has often been characterized with a loss of epithelial markers (E-cadherin) and an increase of mesenchymal markers (Vimentin and N-cadherin). In the western blotting analysis, the expression level of E-cadherin was significantly upregulated compared with that in the control group, whereas the expression levels of N-cadherin and Vimentin were downregulated. Thus, it was suggested that the underlying mechanism of SM inhibits migration and invasion in HepG2 cells and is associated with suppression of EMT.

Solamargine triggers hepatoma cell death through apoptosis.

Solamargine (SM), a steroidal alkaloid glycoside extracted from the traditional Chinese herb Solanum incanum, has been evidenced to inhibit the growth and induce apoptosis in a number of human cancer cell lines. In the present study, the anticancer effect of SM and underlying molecular mechanism of SM-induced apoptosis were investigated on the human hepatocellular carcinoma cells, SMMC7721 and HepG2. The proliferation effects of SM on the SMMC7721 and HepG2 cell lines were evaluated using MTT and colony formation assays. In addition, the percentage of apoptosis was measured using an Annexin V/propidium iodide staining method and the cell cycle distribution mediated by SM was analyzed using flow cytometry. The expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, caspase-9, proliferating cell nuclear antigen (pcna) and Ki67 proteins were examined to further demonstrate the proliferate and apoptosis effects of SM on the hepatoma cells. The results indicated that SM effectively inhibited hepatoma cell proliferation and promoted apoptosis. SM resulted in cell cycle arrest at the G2/M phase in the two cell lines. In addition, SM downregulated the levels of proliferation-associated (Ki67 and pcna) and anti-apoptotic (Bcl-2) proteins, and promoted the activity of apoptosis-associated proteins (Bax, caspase-3 and caspase-9). Therefore, the activation of the Bcl-2/Bax and caspase signaling pathways may be involved in the SM-induced apoptosis of hepatoma cells.