BEC5 Abstracts 3

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Pathology in hamsters administered Solanum plant species that contain steroidal alkaloids.
            (Baker et al., 1989) Download
Syrian hamsters were orally administered ground plant material from either Solanum sarrachoides, S. melongena, S. eleagnifolium, or S. dulcamara. Six of eight hamsters administered S. eleagnifolium and eight of 10 hamsters administered S. dulcamara died following administration of plant material and had gastric glandular mucosal necrosis and small intestinal mucosal necrosis with little inflammation. Hamsters administered S. sarrachoides or S. melongena did not die and had only lesions compatible with gastric distension. Both S. eleagnifolium and S. dulcamara contained solasodine glycoalkaloids(s), and S. dulcamara also contained an equal amount of other glycoalkaloids which were probably derived from soladulcidine (dihydrosolasodine). The lesions produced by these two plants were similar to those reported earlier to be caused by sprout material of S. tuberosum (in which solanidane alkaloids predominate) and by an alkaloid extract of S. tuberosum sprouts. Because of similarities in saponin-like activity and structure of solasodine glycoalkaloids to the solanidine glycoalkaloids of potato sprouts, the glycoalkaloids of S. dulcamara and S. eleagnifolium were probably the agents responsible for the lesions observed.

Antitumour effects of glycoalkaloids isolated from Solanum sodomaeum.
            (Cham et al., 1987)  Download
Glycoalkaloids extracted from Solanum sodomaeum L. show antineoplastic activity against Sarcoma 180 in mice. Aproximately 33% of the total glycoalkaloid content consisted of the triglycoside solasonine and 3% of the triglycoside solamargine. The remainder was a mixture of mono- and diglycosides in which thea glycone was solasodine. Single dose studies of these glycoalkaloids with mice containing Sarcoma 180 indicated that the ED 50 was 9mg/kg, whereas the LD50 was 30mg/kg resulting in a therapeutic index of 3.3. Single dosages of 8 mg/kg given on two consecutive days resulted in inhibition of tumour progresion with greater than 40% survival. In contrast, the use of the same dosages given on thre or four consecutive days resulted in greaterthan 90% survival.


 

Inhibition of Trypanosoma cruzi growth in vitro by Solanum alkaloids: a comparison with ketoconazole.
            (Chataing et al., 1998) Download
The glycoalkaloids alpha-chaconine, alpha-solamargine, alpha-solanine, solasonine, sycophantine, and tomatine, as well as the aglycones demissidine, solanidine, solanocapsine, solasodine, tomatidine, and veratrine were tested as growth inhibitors of Trypanosoma cruzi, strain EP, in LIT medium. Their activity was compared with the antifungal ketoconazole. Glycoalkaloids containing alpha-chacotriose showed trypanolytic activity against the epimastigote form and trypanocidal activity against the bloodstream and metacyclic trypomastigote form of Trypanosoma cruzi in culture medium in micromolar concentrations. Ketoconazole showed a lower activity, at the same concentrations of alpha-chaconine and alpha-solamargine. The observations indicate that the initial target of the compound is at the membrane level with a concomitant change in the parasite morphology. Moreover, internal compartments of the parasites were observed to be affected by the drugs, revealing the dissolution of some organelles as mitocondrias and glycosomes.

Basal cell carcinoma: an evidence-based treatment update.
            (Clark et al., 2014) Download
BACKGROUND:  Basal cell carcinoma (BCC) is the most common skin cancer. Surgical excision remains the standard of treatment, but several alternative treatment modalities exist. OBJECTIVES:  This review aims to provide a current analysis of evidence for the treatment of BCC; specifically, which treatments have the lowest recurrence rates and the best cosmetic outcomes. METHODS:  We searched PubMed (January 1946 to August 2013), Ovid MEDLINE (2003-August 2013), the Cochrane Central Register of Controlled Trials (January 1993 to August 2013), and the Cochrane Database of Systematic Reviews (The Cochrane Library Issue 9, 2013) databases for randomized controlled trials, systematic reviews, or comparative studies for the treatment of BCC. RESULTS:  We found 615 potential articles. Two independent reviewers selected 40 studies: 29 randomized controlled trials (RCTs), seven systematic reviews, and four nonrandomized prospective trials. Treatment modalities reviewed include surgical therapy, radiotherapy and cryotherapy, photodynamic therapy (PDT), topical imiquimod, topical 5-fluorouracil (5-FU), topical solasodine glycoalkaloids, topical ingenol mebutate, intralesional 5-FU, intralesional interferon (IFN), and oral hedgehog pathway inhibitors. CONCLUSIONS:  The available data suggest that surgical methods remain the gold standard in BCC treatment, with Mohs micrographic surgery typically utilized for high-risk lesions. Suitable alternate treatment options for appropriately selected primary low-risk lesions may include PDT, cryotherapy, topical imiquimod, and 5-FU. Radiotherapy is a suitable alternate for surgical methods for treatment in older patient populations. Electrodesiccation and curettage (ED&C) is a commonly used primary treatment option for low-risk lesions; however, there were no RCTs examining ED&C that met our inclusion criteria. New hedgehog pathway inhibitors are promising for the management of advanced BCC; however, side effects are a concern for some patients, and much remains to be learned regarding optimal treatment length, risk of recurrence, and potential development of resistance. There is insufficient evidence at present to make recommendations on topical solasodine glycoalkaloids, topical ingenol mebutate, and intralesional 5-FU and IFN-α. Overall continued research on the efficacy of treatment modalities is needed. In particular, studies should include histologic ascertainment of clearance, long-term follow-up, stratification based on tumor subtype, and comparison with surgical outcomes.

A preliminary assessment of the toxic and mutagenic potential of steroidal alkaloids in transgenic mice.
            (Crawford and Myhr, 1995) Download
Impregnated CD2 transgenic mice, which contain multiple copies of a lambda gt10lacZ construct integrated into the genome of each cell, were given a predetermined estimated maximum tolerated dose of several steroidal alkaloids: Solanum glycoalkaloids from potato, alpha-chaconine and alpha-solanine; aglycones, solanidine and solasodine, and a Veratrum alkaloid, jervine. Observations were made of dams and foetuses for indications of toxicity and/or terata; some dam livers and foetuses were assayed for mutagenicity using the lacZ gene. Other dams were gavaged with a single dose of 75 mg all-trans-retinol/kg to serve as a reference teratogen. Unexpectedly, this level of retinol was not clearly teratogenic. The results of both positive and non-positive selection systems showed that the mutation frequencies in the livers of the dams dosed with alpha-chaconine, alpha-solanine and solanidine were three to four times higher than historically normal in the livers of this transgenic mouse strain.

Feeding of potato, tomato and eggplant alkaloids affects food consumption and body and liver weights in mice.
            (Friedman et al., 1996) Download
Reduced liver weight was used to evaluate the potential toxicity in mice of four naturally occurring steroidal glycoalkaloids: alpha-chaconine and alpha-solanine, alpha-tomatine and solasonine. Increased liver weights was used to evaluate the three corresponding steroidal aglycones: solanidine, tomatidine, and solasodine and the non-alkaloid adrenal steroid dehydroepiandrosterone (DHEA). Adult female Swiss-Webster mice were fed diets containing test compound concentrations of 0 (control), 1.2, 2.4 or 4.8 mmol/kg diet for 7, 14 or 28 d. Absolute liver weights (LW) and relative liver weights (liver weight/body weight x 100, %LW/BW) were determined at autopsy. The %LW/BW was lower than that of controls in mice fed the potato glycoalkaloid alpha-chaconine (-10%, P < or = 0.05) for 7 d with the 2.4 mmol/kg diet dose. Under these same conditions, %LW/BW was greater than that of controls in mice fed two aglycones: solanidine (27%, P < or = 0.001) and solasodine (8%, P < or = 0.01). Relative liver weight increases induced by the aglycones were determined under time and dose conditions in which differences in body weight and food consumption were not significant (2.4 mmol/kg diet for 28 d). Under these conditions, the observed %LW/BW increases relative to the controls were as follows: solanidine (32%, P < or = 0.001), solasodine (22%, P < or = 0.001) and DHEA (16%, P < or = 0.001). Solanidine, solasodine and DHEA were equally potent and were more potent than tomatidine. We also observed that the greater %LW/BW in mice fed 2.4 mmol/kg diet solasodine or solanidine for 14 d declined to near control values if they were fed control diets for another 14 d. The increase in relative liver weight induced by solanidine and solasodine is a reversible adaptive response. These findings and the apparent effects of structure on biological activity should serve as a guide for the removal of the most toxic ++compounds from plant foods. The implications of the results for food safety and health are discussed.

Treatment of Bowen's disease on the penis with low concentration of a standard mixture of solasodine glycosides and liquid nitrogen.
            (Goldberg et al., 2011) Download
The most common form of penile cancer is squamous cell carcinoma (SCC). Due to the high risk for lymph node metastases, penile SCC is usually treated aggressively with Mohs micrographic surgery, excision with wide margins, or penectomy. These procedures have the potential for disfigure- ment and dysfunction of male genitalia, with associated psychological distress. Therefore, when treating superficial SCC (Bowen’s disease) of the penis, a more conservative approach is feasible and often desired by the patient. Nonsurgical treatment options include topical 5-fluorouracil, imiquimod, neodymium-doped yttrium aluminium garnet (Nd:YAG) or carbon dioxide (CO2) laser, and localized radiation. Here, we report a case of Bowen’s disease of the penis successfully treated us- ing a combination approach with a standard mixture of solasodine glycosides (BEC5) and supplemental liquid nitrogen used only on thickened, verrucous genital warts that were also present on the penis.

Aglycone solanidine and solasodine derivatives: A natural approach towards cancer.
            (Hameed et al., 2017) Download
Over the past few years, it was suggested that a rational approach to treat cancer in clinical settings requires a multipronged approach that augments improvement in systemic efficiency along with modification in cellular phenotype leads to more efficient cell death response. Recently, the combinatory delivery of traditional chemotherapeutic drugs with natural compounds proved to be astonishing to deal with a variety of cancers, especially that are resistant to chemotherapeutic drugs. The natural compounds not only synergize the effects of chemotherapeutics but also minimize drug associated systemic toxicity. In this review, our primary focus was on antitumor effects of natural compounds. Previously, the drugs from natural sources are highly precise and safer than drugs of synthetic origins. Many natural compounds exhibit anti-cancer potentials by inducing apoptosis in different tumor models, in-vitro and in-vivo. Furthermore, natural compounds are also found equally useful in chemotherapeutic drug resistant tumors. Moreover, these Phyto-compounds also possess numerous other pharmacological properties such as antifungal, antimicrobial, antiprotozoal, and hepatoprotection. Aglycone solasodine and solanidine derivatives are the utmost important steroidal glycoalkaloids that are present in various Solanum species, are discussed here. These natural compounds are highly cytotoxic against different tumor cell lines. As the molecular weight is concerned; these are smaller molecular weight chemotherapeutic agents that induce cell death response by initiating apoptosis through both extrinsic and intrinsic pathways.


 

Early detection and treatment of skin cancer.
            (Jerant et al., 2000)  Download
The incidence of skin cancer is increasing by epidemic proportions. Basal cell cancer remains the most common skin neoplasm, and simple excision is generally curative. Squamous cell cancers may be preceded by actinic keratoses-premalignant lesions that are treated with cryotherapy, excision, curettage or topical 5-fluorouracil. While squamous cell carcinoma is usually easily cured with local excision, it may invade deeper structures and metastasize. Aggressive local growth and metastasis are common features of malignant melanoma, which accounts for 75 percent of all deaths associated with skin cancer. Early detection greatly improves the prognosis of patients with malignant melanoma. The differential diagnosis of pigmented lesions is challenging, although the ABCD and seven-point checklists are helpful in determining which pigmented lesions require excision. Sun exposure remains the most important risk factor for all skin neoplasms. Thus, patients should be taught basic "safe sun" measures: sun avoidance during peak ultraviolet-B hours; proper use of sunscreen and protective clothing; and avoidance of suntanning.

Basal cell carcinoma: treatment options and prognosis, a scientific approach to a common malignancy.
            (Kuijpers et al., 2002)  Download
The incidence of basal cell carcinoma is rapidly increasing and a number of treatment modalities are available. Treatment of basal cell carcinoma includes both surgical and nonsurgical approaches, some of which are traditional, and others experimental. The treatment modality utilized is dependent on both the tumor type and the patient. In order to choose between therapies, evidence-based research is necessary. In an extensive review of the literature concerning treatment options for patients with basal cell carcinoma, we found that there are a limited number of comparative, prospective, randomized, long-term follow-up studies. Based on the results of the available studies, surgical excision, Mohs surgery and cryosurgery are the three standard therapies of choice. Other treatment modalities should be considered secondary choices. There are also promising new treatment options, such as photodynamic therapy, which need further investigation. Special attention is needed when treating the more aggressive subtypes of the disease, such as the micronodular, infiltrative, adenoid and morpheic forms of basal cell carcinoma, as well as bigger basal cell carcinomas and basal cell carcinoma recurrences.

Steroidal glycosides from the underground parts of Solanum sodomaeum.
            (Ono et al., 2006)  Download
A new steroidal glycoside has been isolated from the underground parts of Solanum sodomaeum L., along with seven known steroidal glycosides. Their chemical structures were determined on the basis of spectroscopic data and chemical evidence, and the structure of one known pregnane type glycoside was corrected. In addition, their antiproliferative activity against human promyelocytic leukemia (HL-60) cells was investigated, and five compounds exhibited stronger activity than cisplatin.

Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma.
            (Rhodes et al., 2007)  Download
OBJECTIVE:  To compare 5-year lesion recurrence rates in primary nodular basal cell carcinoma treated with topical methyl aminolevulinate photodynamic therapy (PDT) or simple excision surgery. DESIGN:  Prospective, randomized, multicenter study. SETTING:  University hospital dermatology departments. PATIENTS:  A total of 97 patients, 50 with 53 lesions treated with methyl aminolevulinate PDT and 47 with 52 lesions treated by excision surgery, were included in the per protocol analysis. Of the lesions treated with methyl aminolevulinate PDT and surgery, 49 and 52, respectively, showed complete clinical response at 3 months after treatment and were observed for long-term outcome evaluation. INTERVENTIONS:  Topical methyl aminolevulinate cream, 160 mg/g, applied for 3 hours before illumination (75 J/cm(2) of red light at 570 to 670 nm) on 2 or 4 occasions (12 [23%] of 53 lesions); or excision surgery. MAIN OUTCOME MEASURES:  Histologically confirmed lesion recurrence, sustained lesion complete response rate (time-to-event analysis), and investigator assessment of cosmetic outcome, 5 years after the last treatment. RESULTS:  At 5 years, recurrence was documented in 7 (14%) of 49 lesions (95% confidence interval [CI], 6%-27%) treated with methyl aminolevulinate PDT vs 2 (4%) of 52 lesions (95% CI, 1%-13%) treated with excision surgery (P = .09). Estimated sustained lesion complete response rates were 76% (95% CI, 59%-87%) and 96% (95% CI, 84%-99%), respectively (P = .01). More patients treated with methyl aminolevulinate PDT than surgery had an excellent or good cosmetic outcome: 27 (87%) of 31 patients (95% CI, 70%-96%) vs 19 (54%) of 35 patients (95% CI, 37%-71%) (P = .007). CONCLUSIONS:  Long-term follow-up indicates superior efficacy of surgery to methyl aminolevulinate PDT in nodular basal cell carcinoma. However, methyl aminolevulinate PDT is also an effective treatment for this indication and exhibits a more favorable cosmetic outcome.

Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.
            (Roozeboom et al., 2012)  Download
BACKGROUND:  Several noninvasive treatment modalities are available for superficial basal cell carcinoma (sBCC). OBJECTIVES:  This systematic review aims to determine residue, recurrence and tumour-free survival probabilities of patients with primary sBCC treated with the currently most frequently used therapies. METHODS:  The PubMed (January 1946 to October 2010), EMBASE (January 1989 to October 2010) and Cochrane (January 1993 to October 2010) databases, and reference lists were searched without date restriction. Inclusion criteria were studies that included primary, histologically proven sBCCs, that reported on residue and/or recurrence probabilities after treatment, and had a minimum follow-up period of 12 weeks. Both randomized and nonrandomized studies were included. The primary and secondary outcomes were the probability of complete response and tumour-free survival, respectively. Two independent reviewers selected 36 studies (14 randomized and 22 nonrandomized), and extracted residue, cumulative recurrence and tumour-free survival probabilities. RESULTS:  Pooled estimates of percentages of sBCC with complete response at 12 weeks post-treatment, derived from 28 studies, were 86.2% [95% confidence interval (CI) 82-90%] for imiquimod treatment, and 79.0% (95% CI 71-87%) for photodynamic therapy (PDT). With respect to tumour-free survival at 1 year, the pooled estimates derived from 23 studies were 87.3% for imiquimod (95% CI 84-91%) and 84.0% for PDT (95% CI 78-90%). Only a small number of studies reported on the results of sBCC treatment with 5-fluorouracil (one), surgical excision (one) and cryotherapy (two). CONCLUSIONS:  Pooled estimates from randomized and nonrandomized studies showed similar tumour-free survival at 1 year for imiquimod and PDT. The PDT tumour-free survival was higher in studies with repeated treatments. However, these results were largely derived from nonrandomized studies, and randomized studies with head-to-head comparison of imiquimod and PDT are lacking. There is a need for head-to-head comparison studies between PDT, imiquimod and other treatments with long-term follow-up to enable better recommendations for optimal sBCC treatment.

Diagnosis and Management of Basal Cell Carcinoma.
            (Tanese, 2019)  Download
OPINION STATEMENT:  Basal cell carcinomas (BCCs) are common skin cancers that tend to appear on sun-exposed skin. Pathobiologically, activation of the Hedgehog signaling pathway characterizes the majority of cases. In general, BCCs are slow-growing and rarely metastasize. Nevertheless, they are locally invasive and can be destructive. While typical cases are diagnosed based on clinical findings, the clinicopathological manifestations are varied. Consequently, skin biopsy is essential to confirm the diagnosis and evaluate the risk of recurrence. In the treatment of primary lesions, the initial goal is to complete tumor removal, whether by conventional surgical excision, Mohs micrographic surgery, cryosurgery, electrodesiccation and curettage, topical application of imiquimod or fluorouracil, photodynamic therapy, or radiation therapy. Of these treatments, surgical excision and Mohs surgery are the most commonly used because of their association with a low recurrence rate and the ability to confirm residual tumor pathologically. However, other treatment options may be preferred according to patient condition, tumor location, and risk of recurrence. In the treatment of metastatic or locally advanced lesions, smoothened inhibitors, which inhibit Hedgehog signaling pathway activation, were recently approved and impressive tumor shrinkage effects have been described. Although the exact prognosis of metastatic BCC has not been analyzed, it is probably poor due to the rarity of such condition. However, emerging molecular targeting agents hold therapeutic promise.

The inactivation of herpes simplex virus by some Solanaceae glycoalkaloids.
            (Thorne et al., 1985) Download
The infectivity of herpes simplex virus Type I in tissue culture was inhibited by prior incubation with aqueous suspensions of glycoalkaloids in order of activity alpha-chaconine greater than alpha-tomatine greater than alpha-solasonine but not by the corresponding aglycones, solanidine, tomatidine and solasodine. However, inhibition was not only dependent on the presence of a sugar moiety since the glycone alpha-solanine was inactive under the conditions used. The glycones, but not the aglycones, showed cytopathic effects on cellular membranes of Vero cells and erythrocytes; therefore, it is suggested that inactivation of virus results from insertion of the glycones into the viral envelope.

Antitumor efficacy of the novel chemotherapeutic agent coramsine is potentiated by cotreatment with CpG-containing oligodeoxynucleotides.
            (van der Most et al., 2006)  Download
Coramsine is a novel chemotherapeutic agent isolated from Solanum linnaeanum (devil's apple). Topical treatment provides clinical benefit for skin tumors. To evaluate the potential broader applicability of the drug, its in vivo anticancer efficacy in a murine model of malignant mesothelioma and its mode of action were investigated. Systemic administration of coramsine slowed tumor growth and prolonged survival time. Importantly, the antitumor efficacy of coramsine was enhanced when treatment was combined with stimulation of innate immunity using unmethylated CpG-containing oligodeoxynucleotides (ODNs). Combination treatment further slowed tumor growth and provided a survival benefit. Coramsine seems to kill tumor cells by direct cell lysis. Using 2 different assays to detect apoptosis (caspase activation and DNA fragmentation), we found no evidence that coramsine induces any form of programmed cell death. The fact that the efficacy of coramsine is potentiated by CpG ODNs suggests that coramsine-induced cell death is an immunologic null event.


 

References

Baker, DC, RF Keeler, and W Gaffield (1989), ‘Pathology in hamsters administered Solanum plant species that contain steroidal alkaloids.’, Toxicon, 27 (12), 1331-37. PubMed: 2629175
Cham, BE, M Gilliver, and L Wilson (1987), ‘Antitumour effects of glycoalkaloids isolated from Solanum sodomaeum.’, Planta Med, 53 (1), 34-36. PubMed: 3575510
Chataing, B, et al. (1998), ‘Inhibition of Trypanosoma cruzi growth in vitro by Solanum alkaloids: a comparison with ketoconazole.’, Planta Med, 64 (1), 31-36. PubMed: 9491766
Clark, CM, M Furniss, and JM Mackay-Wiggan (2014), ‘Basal cell carcinoma: an evidence-based treatment update.’, Am J Clin Dermatol, 15 (3), 197-216. PubMed: 24733429
Crawford, L and B Myhr (1995), ‘A preliminary assessment of the toxic and mutagenic potential of steroidal alkaloids in transgenic mice.’, Food Chem Toxicol, 33 (3), 191-94. PubMed: 7896228
Friedman, M, PR Henika, and BE Mackey (1996), ‘Feeding of potato, tomato and eggplant alkaloids affects food consumption and body and liver weights in mice.’, J Nutr, 126 (4), 989-99. PubMed: 8613903
Goldberg, LH, et al. (2011), ‘Treatment of Bowen’s disease on the penis with low concentration of a standard mixture of solasodine glycosides and liquid nitrogen.’, Dermatol Surg, 37 (6), 858-61. PubMed: 21605251
Hameed, A, et al. (2017), ‘Aglycone solanidine and solasodine derivatives: A natural approach towards cancer.’, Biomed Pharmacother, 94 446-57. PubMed: 28779706
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Rhodes, LE, et al. (2007), ‘Five-year follow-up of a randomized, prospective trial of topical methyl aminolevulinate photodynamic therapy vs surgery for nodular basal cell carcinoma.’, Arch Dermatol, 143 (9), 1131-36. PubMed: 17875873
Roozeboom, MH, et al. (2012), ‘Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials.’, Br J Dermatol, 167 (4), 733-56. PubMed: 22612571
Tanese, K (2019), ‘Diagnosis and Management of Basal Cell Carcinoma.’, Curr Treat Options Oncol, 20 (2), 13. PubMed: 30741348
Thorne, HV, GF Clarke, and R Skuce (1985), ‘The inactivation of herpes simplex virus by some Solanaceae glycoalkaloids.’, Antiviral Res, 5 (6), 335-43. PubMed: 3004327
van der Most, RG, et al. (2006), ‘Antitumor efficacy of the novel chemotherapeutic agent coramsine is potentiated by cotreatment with CpG-containing oligodeoxynucleotides.’, J Immunother, 29 (2), 134-42. PubMed: 16531814