BEC5 Abstracts 1

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Chemical and pharmacological investigation of Solanum species of Brazil--a search for solasodine and other potentially useful therapeutic agents.
            (Barbosa-Filho et al., 1991)  Download
A systematic search for solasodine, an important starting material for the partial synthesis of steroidal hormones as well as other potentially bioactive constituents of various Solanum species of Brazil has been undertaken. Thus, the fruits of S. paludosum, S. asperum, S. sessiliflorum and Solanum sp. were found to contain significant amounts of solasodine. The root bark of S. paludosum which showed curare like activity yielded tomatidenol and another yet unidentified alkaloid responsible for the biological activity. The fruits of S. asperum yielded a new spirosolane alkaloid, solaparnaine. The stem bark of S. pseudo-quina showed convulsive and excitatory activity from which (25S)-isosolafloridine was identified as the active principle. In addition, the latter alkaloid was also found to show antimicrobial activity.

Antibiotic action of Solanum incanum Linnaeus
            (Beaman-Mbaya and Muhammed, 1976)  Download
The fruits of Solanum incanum Linnaeus are extensively used in Kenya for the treatment of cutaneous mycotic infections and other pathological conditions. The therapeutic activity of the berries has been attributed to their content of solanine and related glycoalkaloids, which are saponins and cytostatic poisons. In the present study, however, a simpler more potent antimicrobial substance with a phosphorylated structure similar to the purine adenine was isolated from the berries. The crystals of this compound were effective inhibitors of the growth of gram-positive and -negative bacteria, yeasts, dermatophytes, and some pathogens of agricultural produce. High concentrations of the substance caused hemolysis of erythrocytes.

Solasodine glycosides. Selective cytotoxicity for cancer cells and inhibition of cytotoxicity by rhamnose in mice with sarcoma 180
            (Cham and Daunter, 1990)  Download
BEC, a standard mixture of solasodine glycosides is effective in vivo against murine sarcoma 180 (S180), whereas the aglycone solasodine at equimolar concentrations is ineffective. The efficacy of BEC against S180 in vivo can be inhibited by rhamnose. Mice which are in their terminal stage with S180 can tolerate and become symptom-free of cancer by single dose administration of BEC at concentrations of BEC three times the LD100 for normal mice. These observations suggest that the binding of solasodine glycosides on tumour cells may be mediated through the monosaccharide rhamnose, which forms part of solasonine, solamargine and di-glycosides of solasodine in BEC. Furthermore, these results provide evidence that BEC selectively destroys tumour cells relative to normal cells in vivo.

Topical treatment of malignant and premalignant skin lesions by very low concentrations of a standard mixture (BEC) of solasodine glycosides
            (Cham et al., 1991)  Download
A cream formulation containing high concentrations (10%) of a standard mixture of solasodine glycosides (BEC) has been shown to be effective in the treatment of malignant and benign human skin tumours. We now report that a preparation (Curaderm) which contains very low concentrations of BEC (0.005%) is effective in the treatment of keratoses, basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin of humans. In an open study, clinical and histological observations indicated that all lesions (56 keratoses, 39 BCCs and 29 SCCs) treated with Curaderm had regressed. A placebo formulation had no effect on a smaller number of treated lesions. Curaderm had no adverse effect on the liver, kidneys or haematopoietic system.

Solasodine rhamnosyl glycosides cause apoptosis in cancer cells. Do they also prime the immune system resulting in long-term protection against cancer
            (Cham and Chase, 2012)  Download
Solasodine rhamnosyl glycosides (SRGs) induce apoptosis in a wide variety of cancer cells and are more effective than many well-established anticancer agents. Combination therapy of SRGs with cisplatin treats cisplatin-resistant cells such as lung cancer and breast cancer cells. Anticancer therapies with SRGs have been used intravenously, intraperitoneally, intralesionally, orally, and topically. Data is now presented that in addition to apoptosis and, perhaps as a consequence thereof, SRGs also have an effect of stimulating lasting immunity against cancer as shown with a mouse model and the terminal cancer Sarcoma 180. Mice were inoculated i. p. with Sarcoma 180. Groups of animals were administered SRGs half an hour after Sarcoma 180 inoculation. Mice treated with Sarcoma 180 but not with SRGs all died within 20 days. Four doses of SRGs caused total remission of Sarcoma 180 activity. Mice that went into remission were then reinoculated 20 days later with the cancer. Ten of twelve SRGs cured-animals were resistant to reinduction of terminal doses of the cancer. In comparison, twelve of twelve mice treated with SRGs without initial Sarcoma 180 activity but which were inoculated with Sarcoma 180 cells 20 days later, all died. In addition to apoptosis, SRGs stimulate lasting immunity against cancer. SRGs could play an important role in clinical management of diseases such a malignancy and also be used as a preventative therapy.

Solasodine glycosides. In vitro preferential cytotoxicity for human cancer cells
            (Daunter and Cham, 1990)  Download
Solamargine [(22R,25R)-spiro-5-en-3 beta-yl-alpha-L-rhamnopyranosyl- (1----2glu)-O-alpha-L-rhamnopyranozyl (1----4glu)-beta-D-glucopyranoze], a glycoside of solasodine preferentially inhibits the uptake of tritiated thymidine by cancer cells. In contrast, solamargine at equivalent concentration, and the mono- and diglycosides of solasodine have a limited effect on the uptake of tritiated thymidine for other cell types, including unstimulated lymphocytes and lymphocytes stimulated with Con A. In contrast the solasodine glycosides do not inhibit the uptake of tritiated thymidine by lymphocytes stimulated with PHA or PWM. The inhibition of tritiated thymidine uptake by solamargine and the mono- and di-glycosides of solasodine are dependent upon their cellular uptake by endogenous endocytic lectins (EELs). The mode of action of the solasodine glycosides, in particular solamargine, appears to be the induction of cell lysis, as determined by morphological examination.

Curaderm.
            (Evans et al., 1989)  Download
In response to Beardmore, we wish to bring to our readers attention the results of our development and research on the treatment of skin leasons with Curaderm.

Effect of feeding solanidine, solasodine and tomatidine to non-pregnant and pregnant mice.
            (Friedman et al., 2003)  Download
The aglycone forms of three steroidal glycoalkaloids-solanidine (derived by hydrolytic removal of the carbohydrate side chain from the potato glycoalkaloids alpha-chaconine and alpha-solanine), solasodine (derived from solasonine in eggplants) and tomatidine (derived from alpha-tomatine in tomatoes)-were evaluated for their effects on liver weight increase (hepatomegaly) in non-pregnant and pregnant mice and on fecundity in pregnant mice fed for 14 days on a diet containing 2.4 mmol/kg of aglycone. In non-pregnant mice, observed ratios of % liver weights to body weights (%LW/BWs) were significantly greater than those of the control values as follows (all values in % vs matched controls+/-S.D.): solanidine, 25.5+/-13.2; solasodine 16.8+/-12.0; and tomatidine, 6.0+/-7.1. The corresponding increases in pregnant mice were: solanidine, 5.3+/-10.7; solasodine, 33.1+/-15.1; tomatidine, 8.4+/-9.1. For pregnant mice (a) body weight gains were less with the algycones than with controls: solanidine, -36.1+/-14.5; solasodine, -17.9+/-14.3; tomatidine, -11.9+/-18.1; (b) litter weights were less than controls: solanidine, -27.0+/-17.1; solasodine, -15.5+/-16.8; tomatidine, no difference; (c) the %LTW/BW ratio was less than that of the controls and was significant only for solasodine, -8.7+/-13.7; and (d) the average weight of the fetuses was less than the controls: solanidine, -11.2+/-15.2; solasodine, -11.4+/-9.4; tomatidine, no difference. Abortion of fetuses occurred in five of 24 pregnant mice on the solanidine and none on the other diets. To obtain evidence for possible mechanisms of the observed in vivo effects, the four glycoalkaloids (alpha-chaconine, alpha-solanine, solasonine and alpha-tomatine) mentioned above and the aglycones solanidine and tomatidine were also evaluated in in vitro assays for estrogenic activity. Only solanidine at 10 microM concentration exhibited an increase in the MCF-7 human breast cancer cell proliferation assay. Generally, the biological effects of solanidine differ from those of the parent potato glycoalkaloids. Possible mechanisms of these effects and the implication of the results for food safety and plant physiology are discussed.


The Genus Solanum: An Ethnopharmacological, Phytochemical and Biological Properties Review.
            (Kaunda and Zhang, 2019)  Download
Over the past 30 years, the genus Solanum has received considerable attention in chemical and biological studies. Solanum is the largest genus in the family Solanaceae, comprising of about 2000 species distributed in the subtropical and tropical regions of Africa, Australia, and parts of Asia, e.g., China, India and Japan. Many of them are economically significant species. Previous phytochemical investigations on Solanum species led to the identification of steroidal saponins, steroidal alkaloids, terpenes, flavonoids, lignans, sterols, phenolic comopunds, coumarins, amongst other compounds. Many species belonging to this genus present huge range of pharmacological activities such as cytotoxicity to different tumors as breast cancer (4T1 and EMT), colorectal cancer (HCT116, HT29, and SW480), and prostate cancer (DU145) cell lines. The biological activities have been attributed to a number of steroidal saponins, steroidal alkaloids and phenols. This review features 65 phytochemically studied species of Solanum between 1990 and 2018, fetched from SciFinder, Pubmed, ScienceDirect, Wikipedia and Baidu, using "Solanum" and the species' names as search terms ("all fields").

Potato glycoalkaloids.
            (Maga, 1980)  Download
This review shall attempt to summarize the significance of glycoalkaloids in potato products. Specific areas that are discussed include the types and distribution of glycoalkaloids identified in potatoes, facts affecting their rates of formation and biosynthesis, control measures to minimize their formation, methods of analysis, and the health implications of such compounds along with their flavor properties.

Consequences of using escharotic agents as primary treatment for nonmelanoma skin cancer.
            (McDaniel and Goldman, 2002)  Download
BACKGROUND:  The use of escharotic or caustic pastes to treat skin cancer is based on the centuries-old observation that selected minerals and plant extracts may be used to destroy certain skin lesions. Zinc chloride and Sanguinaria canadensis (bloodroot) are 2 agents that are used as part of the Mohs chemosurgery fixed-tissue technique. The use of escharotics without surgery has been discredited by allopathic medicine but persists and is promoted among alternative practitioners. Patients may now purchase "herbal supplements" for the primary self-treatment of skin cancer, and physicians will see patients who elect this therapy for their skin cancers. OBSERVATIONS:  We reviewed the history of escharotic use for skin disease and performed an Internet search for the availability and current use of escharotics. Our search located numerous agents for purchase via the Internet that are advertised as highly successful treatments for skin cancer. We report 4 cases from our practice in which escharotic agents were used by patients to treat basal cell carcinomas in lieu of the recommended conventional treatment. One patient had a complete clinical response, but had a residual tumor on follow-up biopsy. A second patient successfully eradicated all tumors, but severe scarring ensued. A third patient disagreed with us regarding his care and was lost to follow-up. One patient presented with a nasal basal cell carcinoma that "healed" for several years following treatment elsewhere with an escharotic agent but recurred deeply and required an extensive resection. The lesion has since metastasized. CONCLUSIONS:  Escharotic agents are available as herbal supplements and are being used by patients for the treatment of skin cancer. The efficacy of these agents is unproven and their content is unregulated. Serious consequences may result from their use. Conventional medicine has an excellent track record in treating skin cancer. Physicians should recommend against the use of escharotic agents for skin cancer, and the Food and Drug Administration should be given the authority to regulate their production and distribution.

In-vitro analysis of free radical scavenging activities and suppression of LPS-induced ROS production in macrophage cells by Solanum sisymbriifolium extracts.
            (More and Makola, 2020)  Download
The current study aims to evaluate the antioxidant, cytotoxicity activities and suppression of LPS-induced oxidative stress production and characterization of phytochemicals in Solanum sisymbriifolium leaf extracts. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis3-ethylbenzothiazoline-6-sulphonic acid (ABTS) radical scavenging activity of the leaves of S. sisymbriifolium extracted with solvents of various polarities viz. water: ethanol, ratio 50: 50; ethyl acetate and dichloromethane, was assessed. The cytotoxicity of the extracts was determined using the [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] (MTT) assay on RAW 264.7 macrophage (Murine) cells and real-time cell analysis (RTCA) xCELLigence system was used for determining cell viability. Cell-based detection of reactive oxygen species (ROS) was investigated utilizing a 2',7'-Dichlorodihydrofluorescein diacetate (H|2|DCF-DA) assay. The DPPH and ABTS scavenging activity results of extracts revealed a dose-dependent response with significantly lower activity in both DPPH and ABTS. The superoxide dismutase (SOD) enzyme activity was then evaluated and extracts displayed a high SOD enzyme activity with 90-50% activity. Cytotoxicity results revealed that S. sisymbriifolium extracts were not toxic to RAW 264.7 macrophage cells at the tested concentrations. All three extracts decreased the production of ROS in macrophage cells. Phytochemical analysis using Fourier-transform infrared spectroscopy (FTIR) indicated the presence of metabolite functional groups which may be responsible for the antioxidant activity. The current study indicates that S. sisymbriifolium contains phytochemicals that scavenge free radicals, with less toxicity, and suppresses the LPS-induced ROS production in RAW 264.7 macrophage cells.


Solasodine glycoalkaloids: a novel topical therapy for basal cell carcinoma. A double-blind, randomized, placebo-controlled, parallel group, multicenter study
            (Punjabi et al., 2008)  Download
OBJECTIVE: To assess the safety and efficacy of a 0.005% mixture of solasodine glycosides (Zycure) in the treatment of basal cell carcinoma. Design Double-blind, randomized, and vehicle-controlled, parallel group study. SETTING: Ten centers in the United Kingdom. Participants Male, n = 50; female, n = 44; age range, 32-95 years (Table 1). INTERVENTION: Ninety-four patients were randomized on a 2 : 1 ratio (n = 62, Zycure; n = 32, vehicle). Histologically confirmed lesions were treated double blinded, twice daily under occlusion with Zycure or vehicle for 8 weeks. Patients were reviewed fortnightly for adverse effects and overall response. Successfully treated patients were followed up at six-month intervals for a year. MAIN OUTCOME MEASURES: The primary efficacy endpoint was histologically confirmed clearance of the basal cell carcinoma (2-mm punch biopsy) at the end of 8-week treatment. RESULTS: Efficacy (intention-to-treat population) at 8 weeks was 66% (41/62) in the Zycure group, compared to 25% (8/32) in the vehicle group (P < 0.001; Cochran-Mantel-Haenszel test). Ninety percent (37/41) of the Zycure group completed follow-up at six-month intervals for 1 year, of whom 78% (29/37) had no recurrence. There were no major treatment-related adverse effects, although 10 patients in Zycure group did not complete the treatment protocol for various reasons. CONCLUSION: We conclude that the solasodine glycoside cream Zycure is a safe therapy for basal cell carcinoma, with a cure rate of 66% at 8 weeks and 78% at 1 year follow-up.

Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway
            (Wu et al., 2011)         Download
BACKGROUND: The Solanum species herbs have been used to treat cancer for centuries; however, the underlying mechanisms and effectiveness in vivo remain unclear. OBJECTIVES: SR-T100, extracted from the Solanum incanum, contains solamargine alkaloid as the main active ingredient. Here, we investigated the apoptosis-inducing effects of SR-T100 for targeting squamous cell carcinoma (SCC) in vitro and in vivo. METHODS: We elucidated the mechanism by which SR-T100 induces apoptosis of human SCCs (A431, SCC4, SCC9, and SCC25) cells. The efficacy and safety issues were addressed regarding topical treatment of SR-T100 on UVB-induced cutaneous SCC of hairless mice and actinic keratoses (AKs) of human. RESULTS: SR-T100 induces apoptosis in human SCCs cell lines by up-regulating the expressions of tumor necrosis factor receptors (TNFRs) and Fas, and downstream adaptors FADD/TRADD of the TNF-alpha and Fas ligand signaling cascades. SR-T100 also triggered the mitochondrial apoptotic pathway, as up-regulated cytochrome c and Bax, down-regulated Bcl-X(L). Animal experiments showed that all papillomas (35/35) and 27 of 30 UVB-induced microinvasive SCCs in hairless mice disappeared within 10 weeks after once-daily application of topical SR-T100. Furthermore, 13 patients, who suffered with 14 AKs, were treated with once-daily topical SR-T100 gel and 10 AKs cured after 16 weeks, showing negligible discomforts. CONCLUSION: Our studies indicate that SR-T100 induces apoptosis of SCC cells via death receptors and the mitochondrial death pathway. The high efficacy of SR-T100 in our preclinical trial suggests that SR-T100 is a highly promising herb for AKs and related disorders.

Solasodine inhibits human colorectal cancer cells through suppression of the AKT/glycogen synthase kinase-3β/β-catenin pathway.
            (Zhuang et al., 2017)  Download
Solasodine is a main active component isolated from Solanum incanum L. that performs a wide range of functions containing anti-oxidant, anti-infection, and neurogenesis promotion. In this study, we explored the influence of solasodine on three types of human colorectal cancer (CRC) cell lines. The results show that solasodine prohibited CRC cell proliferation dose- and time-dependently and impeded CRC cell motility by downregulating MMPs. Solasodine was also found to fuel caspase-cascade reaction and increase the ratio between Bax and Bcl-2 so as to induce CRC cell apoptosis. When cells were pretreated with AKT activator (insulin-like growth factor-1) followed by solasodine, the solasodine-induced apoptosis was partially abrogated by insulin-like growth factor-1. Moreover, solasodine hindered tumor development and stimulated similar mechanisms in vivo. In general, our study provides the first evidence that solasodine has a suppressive effect on CRC cells and that this agent may be a novel therapeutic drug for CRC treatment.

Solasodine reverses stemness and epithelial-mesenchymal transition in human colorectal cancer.
            (Zhuang et al., 2018)  Download
Adverse side effects of conventional chemotherapy, acquired resistance and fatal tumor metastasis of human colorectal cancer (CRC) are propelling the exploration for novel selective anticarcinogens. Solasodine is a main active component isolated from Solanum incanum L that exhibited a potent stemness and invasion inhibitory effect on human colorectal cancer HCT116 cells. Colony Spheroid formation assay showed that solasodine dose-dependently prohibited HCT116 cell stemness. CD133, CD44, Nanog, Oct-4 and Sox-2 were inhibited by solasodine to reverse stemness and similar mechanism was stimulated in vivo. Transwell and scratch wound assays revealed that solasodine impeded HCT116 cell invasion and migration potential strengthened by TGF-β1. Moreover, solasodine attenuated TGF-β1-induced EMT and decreased MMPs while in vivo study showed the same trend. The results of this study implied that solasodine may be a novel therapeutic drug for CRC treatment.

 


References

Barbosa-Filho, JM, et al. (1991), ‘Chemical and pharmacological investigation of Solanum species of Brazil--a search for solasodine and other potentially useful therapeutic agents.’, Mem Inst Oswaldo Cruz, 86 Suppl 2 189-91. PubMed: 1841999
Beaman-Mbaya, V and SI Muhammed (1976), ‘Antibiotic action of Solanum incanum Linnaeus.’, Antimicrob Agents Chemother, 9 (6), 920-24. PubMed: 945715
Cham, BE and B Daunter (1990), ‘Solasodine glycosides. Selective cytotoxicity for cancer cells and inhibition of cytotoxicity by rhamnose in mice with sarcoma 180.’, Cancer Lett, 55 (3), 221-25. PubMed: 2257540
Cham, BE, B Daunter, and RA Evans (1991), ‘Topical treatment of malignant and premalignant skin lesions by very low concentrations of a standard mixture (BEC) of solasodine glycosides.’, Cancer Lett, 59 (3), 183-92. PubMed: 1913614
Cham, BE and TR Chase (2012), ‘Solasodine rhamnosyl glycosides cause apoptosis in cancer cells. Do they also prime the immune system resulting in long-term protection against cancer’, Planta Med, 78 (4), 349-53. PubMed: 22399274
Daunter, B and BE Cham (1990), ‘Solasodine glycosides. In vitro preferential cytotoxicity for human cancer cells.’, Cancer Lett, 55 (3), 209-20. PubMed: 2257539
Evans, R, BE Cham, and B Daunter (1989), ‘Curaderm.’, Med J Aust, 150 (6), 350-51. PubMed: 2716652
Friedman, M, PR Henika, and BE Mackey (2003), ‘Effect of feeding solanidine, solasodine and tomatidine to non-pregnant and pregnant mice.’, Food Chem Toxicol, 41 (1), 61-71. PubMed: 12453729
Kaunda, JS and YJ Zhang (2019), ‘The Genus Solanum: An Ethnopharmacological, Phytochemical and Biological Properties Review.’, Nat Prod Bioprospect, 9 (2), 77-137. PubMed: 30868423
Maga, JA (1980), ‘Potato glycoalkaloids.’, Crit Rev Food Sci Nutr, 12 (4), 371-405. PubMed: 6996922
McDaniel, S and GD Goldman (2002), ‘Consequences of using escharotic agents as primary treatment for nonmelanoma skin cancer.’, Arch Dermatol, 138 (12), 1593-96. PubMed: 12472348
More, GK and RT Makola (2020), ‘In-vitro analysis of free radical scavenging activities and suppression of LPS-induced ROS production in macrophage cells by Solanum sisymbriifolium extracts.’, Sci Rep, 10 (1), 6493. PubMed: 32300192
Punjabi, S, et al. (2008), ‘Solasodine glycoalkaloids: a novel topical therapy for basal cell carcinoma. A double-blind, randomized, placebo-controlled, parallel group, multicenter study.’, Int J Dermatol, 47 (1), 78-82. PubMed: 18173610
Wu, CH, et al. (2011), ‘Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway.’, J Dermatol Sci, 63 (2), 83-92. PubMed: 21612892
Zhuang, YW, et al. (2017), ‘Solasodine inhibits human colorectal cancer cells through suppression of the AKT/glycogen synthase kinase-3β/β-catenin pathway.’, Cancer Sci, 108 (11), 2248-64. PubMed: 28803443
Zhuang, YW, et al. (2018), ‘Solasodine reverses stemness and epithelial-mesenchymal transition in human colorectal cancer.’, Biochem Biophys Res Commun, 505 (2), 485-91. PubMed: 30268504