Alkalihalobacillus clausii PA21 transcriptome profiling and functional analysis revealed the metabolic pathway involved in glycoalkaloids degradation.

Glycoalkaloids (GAs), including α-solanine and α-chaconine, are secondary metabolites found in potato, which are toxic to higher animals. In a previous study, Alkalihalobacillus clausii PA21 showed the capacity to degrade GAs. Herein, the transcriptome response of PA21 to α-solanine or α-chaconine was evaluated. In total, 3170 and 2783 differential expressed genes (DEGs) were found in α-solanine- and α-chaconine-treated groups, respectively, with most DEGs upregulated. Moreover, GAs activated transmembrane transport, carbohydrate metabolism, transcription, quorum sensing, and bacterial chemotaxis in PA21 to withstand GA-induced stress and promote GAs degradation. Furthermore, qRT-PCR analysis confirmed the upregulation of degrading enzymes and components involved in GA degradation in PA21. In addition, the GAs-degrading enzymes were heterologous expressed, purified, and incubated with GAs to analyze the degradation products. The results showed that α-solanine was degraded to ß1-solanine, ß2-solanine, γ-solanine, and solanidine by ß-glucosidase, α-rhamnosidase, and ß-galactosidase. Meanwhile, α-chaconine was degraded to ß1-chaconine, ß2-chaconine, γ-chaconine, and solanidine by ß-glucosidase and α-rhamnosidase. Overall, the molecular mechanism underlying GAs degradation by PA21 was revealed by RNAseq combined with protein expression and function studies, thus providing the basis for the development of engineered bacteria that can efficiently degrade GAs to promote their application in the control of GAs in potatoes.

Solanine Represses Gastric Cancer Growth by Mediating Autophagy Through AAMDC/MYC/ATF4/Sesn2 Signaling Pathway.

Purpose: Solanine is the main component of the plant Solanum, which has been shown to provide growth-limiting activities in a variety of human cancers. However, little is known about its function in gastric cancer (GC). Methods: We investigated the effect of solanine on GC in vivo and in vitro. The inhibition rate of solanine on the tumor was observed by constructing a subcutaneous tumor in nude mice. Morphological changes were analyzed with H&E staining. The expression of ATF4 was detected by IF analysis. MTT assays, EdU staining, and colony formation assays were used to detect the inhibition rate of solanine on GC cells. Matrigel transwells were used to detect the invasion of GC cells. Cell migration was measured using the wound healing assay. The flow cytometric analysis was used to monitor changes in the cell cycle and cell apoptosis. Western blotting was used to detect major proteins in cells and tumors. Results: Solanine suppressed gastric tumorigenesis. Solanine also inhibited the proliferation, invasion and mitigation of GC cells, and induced cell cycle arrest and apoptosis in vitro. Moreover, the growth-limiting activities of solanine in gastric cancer were related to the suppression of the AAMDC/MYC/ATF4/Sesn2 pathway-mediated autophagy. Overexpression of AAMDC reversed the inhibitory effect of solanine on autophagy and gastric cancer. Conclusion: In summary, our findings indicate that solanine confers growth-limiting activities by deactivating the AAMDC-regulated autophagy in gastric cancer.

Anti-Cancer Role of Dendrosomal Nano Solanine in Chronic Myelogenous Leukemia Cell Line through Attenuation of PI3K/AKT/mTOR Signaling Pathway and Inhibition of hTERT Expression.

BACKGROUND: Solanine was primarily known as a toxic compound. Nonetheless, recently the apoptotic role of solanine through suppression of PI3K/AKT/mTOR signaling pathway has been shown against many malignancies except chronic myelogenous leukemia (CML). Sustaining the aforementioned pro-survival pathway, BCR-ABL fused oncoprotein in CML activates NF-kB and c- MYC for apparent immortalizing factor hTERT. Since solanine is a poor water-soluble molecule, herein, a nanocarrier was employed to intensify its pernicious effect on cancerous cells. OBJECTIVE: The current research aimed at evaluating the effect of dendrosomal nano solanine (DNS) on leukemic and HUVEC cells. METHODS: DNS characterization was determined by NMR, DLS and TEM. The viability, apoptosis and cell cycle of DNS and imatinib-treated cells were determined. A quantitative real-time PCR was employed to measure the expression of PI3K, AKT, mTOR, S6K, NF-kB, c-MYC and hTERT mRNAs. The Protein levels were evaluated by western blot. RESULTS: Investigating the anticancer property of free and dendrosomal nano solanine (DNS) and the feasible interplaying between DNS and imatinib on leukemic cells, we figured out the potential inhibitory role of DNS and DNS+IM on cancerous cells in comparison with chemotherapy drugs. Moreover, results revealed that the encapsulated form of solanine was much more preventive on the expression of PI3KCA, mTOR, NF-kB, c-MYC and hTERT accompanied by the dephosphorelating AKT protein. CONCLUSION: The results advocate the hypothesis that DNS, rather than solanine, probably due to impressive penetration, can restrain the principal pro-survival signaling pathway in erythroleukemia K562 and the HL60 cell lines and subsequently declined mRNA level of hTERT which causes drug resistance during long-term treatment. Additionally, combinational treatment of DNS and IM could also bestow an additive anti-leukemic effect. As further clinical studies are necessary to validate DNS efficacy on CML patients, DNS could have the potency to be considered as a new therapeutic agent even in combination with IM.

Solanaceae glycoalkaloids: α-solanine and α-chaconine modify the cardioinhibitory activity of verapamil.

CONTEXT: Solanaceae glycoalkaloids (SGAs) possess cardiomodulatory activity. OBJECTIVE: This study investigated the potential interaction between verapamil and glycoalkaloids. MATERIAL AND METHODS: The cardioactivity of verapamil and glycoalkaloids (α-solanine and α-chaconine) was tested in adult beetle (Tenebrio molitor) myocardium in vitro using microdensitometric methods. The myocardium was treated with pure substances and mixtures of verapamil and glycoalkaloids for 9 min with saline as a control. Two experimental variants were used: simultaneous application of verapamil and glycoalkaloids or preincubation of the myocardium with one of the compounds followed by perfusion with a verapamil solution. We used 9 × 10-6-5 × 10-5 M and 10-9-10-5 M concentration for verapamil and glycoalkaloids, respectively. RESULTS: Verapamil, α-solanine and α-chaconine showed cardioinhibitory activity with IC50 values equal to 1.69 × 10-5, 1.88 × 10-7 and 7.48 × 10-7 M, respectively. When the glycoalkaloids were applied simultaneously with verapamil, an antagonistic effect was observed with a decrease in the maximal inhibitory effect and prolongation of t50 and the recovery time characteristic of verapamil. We also confirmed the expression of two transcript forms of the gene that encodes the α1 subunit of L-type calcium channels in the myocardium and brain with equal transcription levels of both forms in the myocardium and significant domination of the shorter form in the brain of the insect species tested. DISCUSSION AND CONCLUSIONS: The results show that attention to the composition of the daily diet during therapy with various drugs is particularly important. In subsequent studies, the nature of interaction between verapamil and SGAs on the molecular level should be checked, and whether this interaction decreases the efficiency of cardiovascular therapy with verapamil in humans.

α-Solanine Inhibits Proliferation, Invasion, and Migration, and Induces Apoptosis in Human Choriocarcinoma JEG-3 Cells In Vitro and In Vivo.

α-Solanine, a bioactive compound mainly found in potato, exhibits anti-cancer activity towards multiple cancer cells. However, its effects on human choriocarcinoma have not been evaluated. In the present study, we investigated the effect of α-solanine on cell proliferation and apoptosis in human choriocarcinoma in vitro and in vivo. The results showed that α-solanine, at concentrations of 30 µM or below, did not affect the cell viability of the choriocarcinoma cell line JEG-3. However, colony formation was significantly decreased and cell apoptosis was increased in response to 30 µM α-solanine. In addition, α-solanine (30 µM) reduced the migration and invasion abilities of JEG-3 cells, which was associated with a downregulation of matrix metalloproteinases (MMP)-2/9. The in vivo findings provided further evidence of the inhibition of α-solanine on choriocarcinoma tumor growth. α-Solanine suppressed the xenograft tumor growth of JEG-3 cells, resulting in smaller tumor volumes and lower tumor weights. Apoptosis was promoted in xenograft tumors of α-solanine-treated mice. Moreover, α-solanine downregulated proliferative cellular nuclear antigen (PCNA) and Bcl-2 levels and promoted the expression of Bax. Collectively, α-solanine inhibits the growth, migration, and invasion of human JEG-3 choriocarcinoma cells, which may be associated with the induction of apoptosis.

α-Solanine Causes Cellular Dysfunction of Human Trophoblast Cells via Apoptosis and Autophagy.

The trophoblast, an embryonic tissue, exerts a crucial role in the processes of implantation and placentation. Toxins in food can cause malfunction of trophoblasts, resulting in apoptosis, oxidative stress, and abnormal angiogenesis. α-solanine, a steroidal glycoalkaloid, has antitumor properties on several cancer cells. However, its effect on human trophoblasts has not been elucidated. In this study, human extravillous trophoblast HTR-8/SVneo cells were exposed to α-solanine. Cellular functions including proliferation, migration, invasion, tube formation, and apoptosis were assessed. To monitor autophagic flux, trophoblasts were transfected with a mCherry-GFP-LC3B vector using lentiviral transduction, and expression of autophagy-related biomarkers including Beclin 1, Atgl3, and microtubule-associated protein 1 light chain-3 (MAP1-LC3) were detected. The results show that application of 20 µM α-solanine or above inhibited the cell viability, migration, invasion, and tube formation of the human trophoblast. Cell cycle was arrested at S and G2/M phases in response to 30 µM α-solanine. α-solanine induced apoptosis of HTR-8/SVneo cells and triggered autophagy by increasing the autophagic gene expression and stimulating the formation of autophagosome and autophagic flux. In conclusion, α-solanine can impair the functions of human trophoblast cells via activation of cell apoptosis and autophagy.

Alpha Solanine: A Novel Natural Bioactive Molecule with Anticancer Effects in Multiple Human Malignancies.

Cancer is one of the leading causes of death worldwide. Despite improvement in existing treatment modalities and addition of new anticancer drugs in the cancer clinic, cancer associated mortalities are continuously increasing. It is therefore, necessary to explore alternative treatment options to reduce the burden of cancer. In recent years, there is growing concern toward the use of natural products for treating cancer because of their ability to target multiple signaling molecules. α-solanine is a glycolalkaloid mainly present in potato tuber and Nightshade family plants. It possesses anti-pyretic, anti-diabetic, anti-allergic, anti-inflammatory and antibiotic activities. In recent years, α-solanine has been explored for its anticancer activity and showed promising results. Among all sources, potato peel contains adequate concentration of α-solanine. Every year, a large volume of potato peel is produced as a waste or sold at low cost. So α-solanine can be proved as an effective and cheap source for cancer therapy. The aim of this review is to summarize the recent data on anticancer activity of α-solanine and discuss it as a potential lead for cancer therapy.

Solanine Inhibits Immune Escape Mediated by Hepatoma Treg Cells via the TGFß/Smad Signaling Pathway.

OBJECTIVE: To observe the inhibitory effect of solanine on regulatory T cells (Treg) in transplanted hepatoma mice and to study the mechanism of solanine inhibiting tumor growth. METHODS: The levels of Treg cells and IL-2, IL-10, and TGFß in the blood of patients with liver cancer were detected by flow cytometry and ELISA, respectively. A mouse hepatocellular carcinoma (HCC) graft model was established and randomly divided into four groups: control group, solanine group, TGFß inhibitor group (SB-431542), and solanine +TGFß inhibitor combined group. Tumor volume of each group was recorded, tumor inhibition rate was calculated, and tumor metastasis was counted. The proportion of CD4+CD25+Foxp3+ Treg in transplanted tumor tissues was detected by flow cytometry. The expression levels of Foxp3 and TGFß in transplanted tumor tissues were detected by quantitative fluorescence PCR. RESULTS: Compared with healthy people, Treg cells and IL-2, IL-10, and TGFß contents in peripheral blood of liver cancer patients were increased. The results of the transplanted tumor model in mice showed that the tumor volume of the transplanted mice in the solanine group and the TGFß inhibitor mice was reduced compared with the control group. The combined group had the smallest tumor volume. The proportion of CD4+CD25+Foxp3+ Treg in the transplanted tumor tissues of mice in the solanine treatment group was significantly lower than that in the control group. The expressions of Foxp3 and TGFß in the transplanted tumor tissues of mice in the solanine group were significantly lower than those in the control group. CONCLUSION: Solanine may enhance the antitumor immune response by downregulating the proportion of CD4+CD25+ Treg and the expression of Foxp3 and TGFß in tumor tissues.

Solanine Attenuates Hepatocarcinoma Migration and Invasion Induced by Acetylcholine.

AIM: Evidence has provided an explanation of the correlation between the nervous system and the tumor microenvironment. Neurotransmitters may be involved in different aspects of cancer progression. The glycoalkaloid solanine has been reported to suppress neural signaling pathways and exists in numerous plants, including Solanum nigrum, which have been demonstrated to inhibit cancer cell proliferation. METHODS: We evaluated the potentials of solanine on inhibiting acetylcholine-induced cell proliferation and migration in hepatocellular carcinoma cells. RESULTS: The results indicated that solanine markedly attenuated cell proliferation and migration via inhibiting epithelial-mesenchymal transition and matrix metalloproteinases in acetylcholine-treated Hep G2 cells. In addition, exosomes derived from acetylcholine-treated Hep G2 cells were isolated, and solanine showed inhibiting effects of extrahepatic metastasis on blocking cell proliferation in exosome-treated A549 lung carcinoma cells through regulating microRNA-21 expression. CONCLUSION: Solanine has strong potential for application in integrative cancer therapy.

Solanine inhibits proliferation and promotes apoptosis of the human leukemia cells by targeting the miR-16/Bcl-2 axis.

PURPOSE: Leukemia causes tremendous human mortality especially in children and young adults. This study was undertaken to investigate the anticancer effects of Solanine against the normal human NCI-H526 and human leukemia AML-193 cell lines. METHODS: Cell proliferation was determined by MTT assay. DAPI and annexin V/propidium iodide (PI) assays were used for the determination of apoptosis. The expression analysis was done by qRT-PCR. Protein concentrations were determined by western blot analysis. RESULTS: DAPI staining showed that Solanine causes nuclear morphological changes. The annexin V/PI staining showed that Solanine increased the leukemia apoptotic cell death dose-dependently. The expression of Bax was increased while of Bcl-2 was decreased. The qRT-PCR analysis showed that microRNA (miR)-16 was significantly (p<0.05) downregulated in leukemia AML-193 cells as compared to normal NCI-H526 cells. CONCLUSION: Taken together, these results showed that Solanine inhibits the proliferation of leukemia cells via induction of apoptosis and modulation of miR-16/Bcl-2 axis.

α­Solanine inhibits growth and metastatic potential of human colorectal cancer cells.

Solanum nigrum L. (Longkui) is one the most widely used anticancer herbs in traditional Chinese medicine. α­Solanine is an important ingredient of S. nigrum L. and has demonstrated anticancer properties in various types of cancer. However, the effects of α­solanine on colorectal cancer remain elusive. The aim of the present study was to assess the effects of α­solanine on human colorectal cancer cells. The results demonstrated that α­solanine inhibited the proliferation of RKO cells in a dose­ and time­dependent manner. In addition, α­solanine arrested the cell cycle at the G0/G1 phase and suppressed the expression levels of cyclin D1 and cyclin­dependent kinase 2 in RKO cells. α­Solanine induced apoptosis of RKO cells, as indicated by morphological changes and positive Annexin­FITC/propidium iodide staining. Additionally, α­solanine activated caspase­3, ­8 and ­9 in RKO cells, which contributed to α­solanine­induced apoptosis. α­Solanine also increased the generation of reactive oxygen species, which contributed to caspase activation and induction of apoptosis. α­Solanine inhibited the migration, invasion and adhesion of RKO cells, as well as the expression levels and activity of matrix metalloproteinase (MMP)­2 and MMP­9. In addition, α­solanine inhibited cell proliferation, activated caspase­3, ­8 and ­9, induced apoptosis, and inhibited the migration and invasion of HCT­116 cells. Furthermore, α­solanine inhibited tumor growth and induced apoptosis in vivo. These findings demonstrated that α­solanine effectively suppressed the growth and metastatic potential of human colorectal cancer.

Synergistic Effect of α-Solanine and Cisplatin Induces Apoptosis and Enhances Cell Cycle Arrest in Human Hepatocellular Carcinoma Cells.

AIM: The clinical application of cisplatin is limited by severe side effects associated with high applied doses. The synergistic effect of a combination treatment of a low dose of cisplatin with the natural alkaloid α-solanine on human hepatocellular carcinoma cells was evaluated. METHODS: HepG2 cells were exposed to low doses of α-solanine and cisplatin, either independently or in combination. The efficiency of this treatment modality was evaluated by investigating cell growth inhibition, cell cycle arrest, and apoptosis enhancement. RESULTS: α-solanine synergistically potentiated the effect of cisplatin on cell growth inhibition and significantly induced apoptosis. This synergistic effect was mediated by inducing cell cycle arrest at the G2/M phase, enhancing DNA fragmentation and increasing apoptosis through the activation of caspase 3/7 and/or elevating the expression of the death receptors DR4 and DR5. The induced apoptosis from this combination treatment was also mediated by reducing the expression of the anti-apoptotic mediators Bcl-2 and survivin, as well as by modulating the miR-21 expression. CONCLUSION: Our study provides strong evidence that a combination treatment of low doses of α-solanine and cisplatin exerts a synergistic anticancer effect and provides an effective treatment strategy against hepatocellular carcinoma.

Long noncoding RNA GAS5 modulates α-Solanine-induced radiosensitivity by negatively regulating miR-18a in human prostate cancer cells.

Radiotherapy is an adjuvant treatment of surgery in prostate cancer, while radioresistance has been the challenge of treatment. It has been reported that α-Solanine exhibits anti-cancer activity and enhances the chemo- and radio-sensitivity in several human cancers, whereas the role of α-Solanine on radiosensitivity to PCa remains to be uncovered yet. We found α-Solanine decreased cell viability in human PCa cells rather than normal prostate epithelial cells in vitro. Functional experiments showed that cell viability and colonies formation were declined & apoptosis rate and DNA double strand breaks (DSBs) marker γ-H2AX expressions were elevated by α-Solanine in PCa cells treated with X-ray irradiation, compared with X-ray irradiation treatment only. GAS5 was down-regulated & miR-18a was up-regulated in PCa cells, which was reversed in the presence of α-Solanine. Effects of ectopic GAS5 on inhibiting cell viability and survival & promoting apoptosis and DNA damage were reversed by miR-18a overexpression in PCa cells. Moreover, GAS5 regulated miR-18a expression by target binding during α-Solanine treatment. Collectively, α-Solanine suppresses cell proliferation and promotes radiosensitivity through up-regulating GAS5/miR-18a pathway in PCa. Our results provide a novel mechanism of α-Solanine treatment in human prostate cancer and help to develop a new approach to sensitizing radioresistant prostate cancer cells by targeting GAS5/miR-18a.

Synthesis and insecticidal activities of novel solanidine derivatives.

BACKGROUND: Potato (Solanum tuberosum) is the fourth culture in the world and is widely used in the agri-food industries. They generate by-products in which α-chaconine and α-solanine, the two major solanidine-based glycoalkaloids of potato, are present. As secondary metabolites, they play an important role in the protection system of potato and are involved in plant protection against insects. To add value to these by-products, we described here new glycoalkaloids that could have phytosanitary properties. RESULTS: Solanidine, as a renewable source, was modified with an azido linker and coupled by copper-catalyzed alkyne azide cycloaddition to alkynyl derivatives of the monosaccharides found in the natural potato glycoalkakoids: D-glucose, D-galactose and L-rhamnose. The efficacy of our compounds was evaluated on the potato aphid Macrosiphum euphorbiae. The synthetic compounds have stronger aphicidal properties against nymphs than unmodified solanidine. They also showed strong aphicidal activities on adults and a negative impact on fecundity. CONCLUSION: Our synthetic neoglycoalkaloids affected Macrosiphum euphorbiae survival at the nymphal stage as well as at the adult stage. Furthermore, they induced a decrease in fecundity. Our results show that chemical modifications of by-products may afford new sustainable compounds for crop and plant protection. © 2018 Society of Chemical Industry.

Emerging themes of regulation of oncogenic proteins by Solanum nigrum and its bioactive molecules in different cancers.

Research over the decades has sequentially and systematically provided a near-complete resolution of multifaceted and therapeutically challenging nature of cancer. Drug discovery from plants has enjoyed a renaissance in the past few years. Natural products have provided many of the lead structures, which are currently being used as templates for the design and synthesis of novel compounds with biologically enhanced properties. With the maturity and diversification of technologies, there is a growing need to design high-throughput functional assays for the evaluation of the myriad of compounds being catalogued. This review sheds light on the tumor suppressive properties of Solanum nigrum and its bioactive ingredients. Several worthy of mention include uttroside B, solanine, solamargine, and physalins, which have been tested for efficacy in cancer cell lines and xenografted mice. We have summarized the most recent findings related to S. nigrum-mediated regulation of intracellular protein network in different cancers. α-Solanine, an active component of S. nigrum, is involved in the regulation of microRNA-21 (miRNA-21) (oncogenic) and miRNA-138 (tumor suppressor) in prostate cancer. However, this is the only available evidence that gives us a clue related to the tumor suppressive effects exerted by components of S. nigrum at a posttranscriptional level. More interestingly, S. nigrum and its components exerted inhibitory effects on different pathways including PI3K/AKT, JAK-STAT, VEGF/VEGFR, and matrix metalloproteinases in different cancers. We also provide an overview of new tools, methodologies, and approaches, which will allow researchers to extract as much information as possible out of the tremendous data sets currently being generated. The use of computational tools will be helpful in processing structurally complex natural products and also in prediction of their macromolecular targets.

α-Chaconine and α-Solanine Inhibit RL95-2 Endometrium Cancer Cell Proliferation by Reducing Expression of Akt (Ser473) and ERα (Ser167).

The aim of this study is to investigate the potential inhibitory effect of α-chaconine and α-solanine on RL95-2 estrogen receptor (ER) positive human endometrial cancer cell line and to identify the effect of these glycoalkaloids on the Akt signaling and ERα. The cell proliferation profiles and the cytotoxicity studies were performed by Real-Time Cell Analyzer (xCELLigence) and compared with Sulphorhodamine B (SRB) assay. The effects of α-chaconine (2.5, 5, 10 µM), α-solanine (20, 30, 50 µM), API-1 (25 µM) and MPP (20 µM) effects on Akt (Ser473) and ERα (Ser167) expressions evaluated by Western blot and qPCR method. Their IC50 values were as α-chaconine (4.72 µM) < MPP (20.01 µM) < α-solanine (26.27 µM) < API-1 (56.67 µM). 10 µM α-chaconine and 20, 30 and 50 µM α-solanine were effective in decreasing p-Akt(Ser473)/Akt ratio compared to positive control API-1. When the p-ERα/ERα ratios were evaluated, it was observed that α-chaconine (2.5, 5, 10 µM) and α-solanine (50 µM) were as effective as the specific ERα inhibitor MPP in reducing the ratio of p-ERα/ERα compared to the control group. In conclusion, it has been shown that the proliferation of α-chaconine and α-solanine in human endometrial carcinoma cells reduces the expression and activity of the Akt and ERα signaling pathway.

The effect of α-solanine on the activity, gene expression, and kinetics of arylamine N-acetyltransferase in HepG2 cells.

α-solanine is one of the major components of Solanum nigrum Linn., the fruits of which are used in China for food. In the present study, α-solanine was selected to assess the inhibition of arylamine N-acetyltransferase (NAT) activity and mRNA expression of NAT and kinetics in HepG2 cells. NAT activity was examined by HPLC. The double-reciprocal plot was contrived to yield a regression equation to calculate Km and Vmax. NAT mRNA expression was determined by PCR. The results revealed that α-solanine could significantly decrease NAT activity in intact HepG2 cells or the cytoplasm. Km did not differ either for intact HepG2 cells or for the cytoplasm, however Vmax was significantly different. α-solanine could decrease the expression of NAT1 mRNA and NAT2 mRNA. In summary, α-solanine was a non-competitive inhibitor of NAT in HepG2 cells. It decreased NAT activity through non-competitive inhibition of NAT activity and by decreasing the expression of NAT1 mRNA and NAT2 mRNA.

Anti-Cancer Effect of α-Solanine by Down-Regulating S100P Expression in Colorectal Cancer Cells.

BACKGROUND: α-Solanine, the most important and active component of Solanum nigrum, was found to have anti-cancer activity on multiple cancer cells. However, its effects on colorectal cancer (CRC) and associated molecular mechanisms remain to be further elucidated. OBJECTIVE: In this study, we investigated the anti-cancer effects of α-solanine against CRC cells in vitro and in vivo. MATERIALS & METHODS: Cell viability was measured using Cell Counting Kit-8 (CCK-8) assay; cell cycle was analyzed with a Cycletest Plus DNA Reagent Kit; cell apoptosis was detected by flow cytometer; cell migration and invasive ability was determined by Transwell assays; S100P protein expression was also analyzed by western blotting; lentiviral vectors expressing shRNA targeting the S100P gene. RESULTS: We demonstrated that α-solanine inhibited CRC cell (SW480, SW620 and HT-29) growth as well as migration and invasion, induced cell cycle arrest and apoptosis in vitro, and suppressed tumor growth in vivo. Moreover, we observed that S100P expression was downregulated by α-solanine. Overexpression of S100P partially reversed the α-solanine-induced growth inhibition of CRC cells. Conversely, knockdown of S100P by lentiviral-mediated RNAi resulted in significantly promoting the α-solanine-induced growth inhibition. CONCLUSION: These findings suggest that α-solanine is a potential agent for the treatment of CRC, and the anti-tumor effect of α-solanine in the CRC cells may be mediated at least partly by the downregulation of S100P.

α-solanine enhances the chemosensitivity of esophageal cancer cells by inducing microRNA­138 expression.

Esophageal cancer is a common malignant tumor worldwide. Inherent and acquired drug resistance are the major challenges faced in anticancer chemotherapy. This study aimed to explore the effects of α-solanine in regards to the chemosensitivity of esophageal cancer cells. We found that α-solanine enhanced the sensitivity of EC9706 and KYSE30 cells to 5-flurouracil (5-FU) and cisplatin (Cis) by promoting drug-induced apoptosis. qRT-PCR and western blotting results showed that α-solanine treatment promoted miR-138 expression and decreased survivin expression in EC9706 and KYSE30 cells. α-solanine also enhanced the inhibitory effects of 5-Fu and Cis in EC9706 transplanted tumors in mouse models. Dual-Luciferase reporter assay results confirmed survivin as the direct target gene of miR-138. MiR-138 inhibited survivin expression in EC9706 and KYSE30 cells. And miR-138 mimic and si-survivin had similar effects with α-solanine in suppressing survivin expression and promoting cancer cell death. miR-138 inhibitor reversed the chemosensitivity-enhancing effect of α-solanine. In EC9706 and KYSE30 cells, survivin overexpression rescued the cancer cells from apoptosis caused by α-solanine and miR-138 mimic expression. From these findings, we conclude that α-solanine enhanced the chemosensitivity of esophageal cancer cells to chemotherapy via the miR-138/survivin pathway. This study provides insight into the molecular mechanism underlying the chemosensitivity-enhancing function of α-solanine and suggests a new chemotherapeutic strategy for esophageal cancer treatment.

α-Solanine reverses pulmonary vascular remodeling and vascular angiogenesis in experimental pulmonary artery hypertension.

OBJECTIVE: Similar to cancer, pulmonary arterial hypertension (PAH) is characterized by vascular remodeling, which leads to obliteration of the small pulmonary arteriole, with marked proliferation of pulmonary artery smooth muscle cells (PASMC) and/or endothelial cells dysfunction. Aberrant expression of tumor suppressor genes is closely associated with susceptibility to PAH. We hypothesized that α-solanine, a glycoalkaloid found in members of the nightshade family known to have antitumor activity in different cancers, reverses experimental PAH by activating the tumor suppressor-axis inhibition protein 2 (AXIN2). METHODS AND RESULTS: We investigated the effects of α-solanine on PASMC proliferation and apoptosis by using 5-ethynyl-2'-deoxyuridine proliferation assay, proliferating cell nuclear antigen and Ki67 staining, TUNEL and Anexine V assays. Scratch wound healing and tube formation assays were also used to study migration of endothelial cells. In vitro, we demonstrated, using cultured human PASMC from PAH patients, that α-solanine reversed dysfunctional AXIN2, ß-catenin and bone morphogenetic protein receptor type-2 signaling, whereas restored [Ca]i, IL-6 and IL-8, contributing to the decrease of PAH-PASMC proliferation and resistance to apoptosis. Meanwhile, α-solanine inhibits proliferation, migration and tube formation of PAH-pulmonary artery endothelial cells by inhibiting Akt/GSK-3α activation. In vivo, α-solanine administration decreases distal pulmonary arteries remodeling, mean pulmonary arteries pressure and right ventricular hypertrophy in both monocrotaline-induced and Sugen/hypoxia-induced PAH in mice. CONCLUSION: This study demonstrates that AXIN2/ß-catenin axis and Akt pathway can be therapeutically targeted by α-solanine in PAH. α-Solanine could be used as a new therapeutic strategy for the treatment of PAH.