Antitumor activity of solamargine in mouse melanoma model: relevance to clinical safety.

Melanoma is the most aggressive type of skin cancer, and thus it is important to develop new drugs for its treatment. The present study aimed to examine the antitumor effects of solamargine a major alkaloid heteroside present in Solanum lycocarpum fruit. In addition solamargine was incorporated into nanoparticles (NP) of yttrium vanadate functionalized with 3-chloropropyltrimethoxysilane (YVO4:Eu3+:CPTES:SM) to determine antitumor activity. The anti-melanoma assessment was performed using a syngeneic mouse melanoma model B16F10 cell line. In addition, systemic toxicity, nephrotoxic, and genotoxic parameters were assessed. Solamargine, at doses of 5 or 10 mg/kg/day administered subcutaneously to male C57BL/6 mice for 5 days, decreased tumor size and frequency of mitoses in tumor tissue, indicative of a decrease in cell proliferation. Treatments with YVO4:Eu3+:CPTES:SM significantly reduced the number of mitoses in tumor tissue, associated with no change in tumor size. There were no apparent signs of systemic toxicity, nephrotoxicity, and genotoxicity initiated by treatments either with solamargine alone or plant alkaloid incorporated into NP. The animals treated with YVO4:Eu3+:CPTES:SM exhibited significant increase in spleen weight accompanied by no apparent histological changes in all tissues examined. In addition, animals treated with solamargine (10 mg/kg/day) and YVO4:Eu3+:CPTES:SM demonstrated significant reduction in hepatic DNA damage which was induced by tumor growth. Therefore, data suggest that solamargine may be considered a promising candidate in cancer therapy with no apparent toxic effects.

In vitro leishmanicidal and cytotoxic activities of the glycoalkaloids from Solanum lycocarpum (Solanaceae) fruits.

Leishmaniasis is an infection caused by a protozoan parasite of the genus Leishmania and is the second most prevalent parasitic protozoal disease after malaria in the world. We report the in vitro leishmanicidal activity on promastigote forms of Leishmania amazonensis and cytotoxicity, using LLCMK2 cells, of the glycoalkaloids from the fruits of Solanum lycocarpum, determined by colorimetric methods. The alkaloidic extract was obtained by acid-base extraction; solamargine and solasonine were isolated by silica-gel chromatography, followed by reversed-phase HPLC final purification. The alkaloidic extract, solamargine, solasonine, as well as the equimolar mixture of the glycoalkaloids solamargine and solasonine displayed leishmanicidal activity against promastigote forms of L. amazonensis, whereas the aglycone solasodine was inactive. After 24 and 72 h of incubation, most of the samples showed lower cytotoxicities (IC50 6.5 to 124 µM) as compared to leishmanicidal activity (IC50 1.1 to 23.6 µM). The equimolar mixture solamargine/solasonine was the most active with an IC50 value of 1.1 µM, after 72 h. Likewise, solamargine was the most active after 24 h with an IC50 value of 14.4 µM, both in comparison with the positive control amphotericin B.

Toxicological effects of alpha-solamargine in experimental animals.

Alpha-solamargine isolated from the fresh fruits of Solanum americanum Miller was studied for its toxicity. Lethality studies in rats showed a dose-mortality relationship with a LD(50) of 42 mg/kg body weight intraperitoneally. The chronic and subchronic toxicity investigations indicated that the size of the glycoalkaloid dose was more important than the total glycoalkaloid intake. No appreciable toxic effects were observed at doses below 35 mg/kg body weight as indicated by blood parameters, enzyme levels and histological sections of kidney, liver and cardiac muscle. Alpha-solamargine did not affect the weight of the testes and epididymis or the number of spermatozoa but produced a slight irritation and congestion in the epididymis and testis at doses up to 50 mg/kg body weight.

Toxicological evaluations of long-term consumption of Solanum lycocarpum St. Hill fruits in male and female adult rats.

Solanum lycocarpum St. Hill is a common plant in the Brazilian savanna. This plant contains an alkaloid with stereospecific configuration to the synthesis of steroid hormones. Because the plant may be consumed long-term, the present study was undertaken to determine the possible toxic effects of S. lycocarpum fruit ingestion (3% added to the diet) on male (60 days of administration) and female (37 days) adult rats. Few significant differences in body weight and consumption of food and water, no significant differences in male and female weight gain or estrous cycle were detected. Female treated rats showed a significant reduction in uterus and liver weights; however, no significant differences were observed in other organ (adrenal, liver, seminal vesicle, testicle and ovary) weights in either sex. Additionally blood enzymes and proteins evaluated were not affected by treatment with 3% S. lycocarpum added to the diet. The present data, however, show sex-related differences in S. lycocarpum toxicity. Thus, other studies have to be conducted to better investigate female toxicity and other toxic effects of higher levels of exposure to this plant.

Assessment of the perinatal effects of maternal ingestion of Solanum malacoxylon in rats.

A perinatal study was performed to verify the toxic effects of Solanum malacoxylon, which contains a glycoside conjugated to Vitamin D(3). In the gestational study, female rats received S. malacoxylon leaves in the diet at 0, 0.1, 0.2, 0.5, and 1% from days 6 to 21 of pregnancy. At 21 days of gestation, blood samples were taken from the dams for evaluation of serum Ca and P. A laparotomy was performed and the rats were examined for standard parameters of reproductive performance. Fetuses were examined for skeletal changes and histopathologic evaluation. In the second trial, dams were fed diets containing 0 or 0.1% S. malacoxylon leaves during the gestation and lactation periods. After weaning, all animals were euthanized and biochemical and histopathologic evaluations were performed. The biochemical evaluation showed increase in Ca and P levels in females from all experimental groups; however, this effect did not occurred in a dose-related manner. Pups from dams exposed during gestation and lactationi also showed increased Ca and P levels. Fetal data suggested a delay of fetal development manifested by decreased body weight and skeletal alterations. There was also a reduction in live fetuses. Histopathologic study revealed alterations of the soft tissue in litters from dams given 1% dietary S. malacoxylon during pregnancy and 0.1% during pregnancy and lactation. These findings support our hypothesis that Vitamin D(3) glycoside crosses the placenta and suggests milk transfer of this substance.

Absence of interceptive effect in rats treated with Solanum lycocarpum (St. Hil).

The interceptive effect of the powder of Solanum lycocarpum (St. Hil) (Solanaceae) fruit, used as a hypoglycemic agent by diabetic patients in Minas Gerais state (Brazil), was evaluated to observe possible effects upon zygote and pre-embryo transport in rats, since it contains solamargine and solasonine from which a 3beta-acetoxipregna-5,16-dien-20-one is obtained as well as an alkaloid with stereospecific configuration to the synthesis of steroid hormones. Inseminated rats received an aqueous suspension of 100 mg of the lobeira powder/kg of body weight, by oral gavage, from the 1st to the 4th day of pregnancy. A control group received 5 mL of distilled water in the same schedule. The pregnant rats were weighed at the beginning of treatment and on sacrifice day. Animals were killed on the 5th day of pregnancy. The oviducts and uterine horns were removed and flushed with saline solution to count expanded blastocysts. It was concluded that administration of lobeira did not cause maternal toxicity, alteration of the pre-embryo transport or reduction of the number of expanded blastocysts.

Effects of plant-induced hypervitaminosis D on cutaneous structure, cell differentiation and cell proliferation in cattle.

Solanum glaucophyllum (Sg) (synonym S. malacoxylon) is a plant toxic to cattle due to its high levels of 1,25-dihydroxyvitamin D3 as glycoside derivatives. Sg causes a disease characterized by wasting and calcification of soft tissues. The effects of vitamin D are not only important in calcium homeostasis, but also in immune regulation, cell growth and cell differentiation. Skin samples in Sg-intoxicated and control heifers were studied histologically. Cellular differentiation and proliferation were analysed by immunohistochemical expression of cytokeratins, involucrin and proliferating cell nuclear antigen (PCNA). The results were obtained by image processing and analysis and were statistically evaluated. Sg-intoxicated cattle showed atrophy of epidermis and severe involution of hair follicles and of sebaceous and sweat glands. As judged by PCNA expression, cellular proliferation was reduced, even though the reduction was not statistically significant. The analysed markers of differentiation, e.g. involucrin and cytokeratins 10 and 11, changed in relation to Sg-poisoning. The possible pathogenesis of the skin lesions is discussed.

Evaluation of the toxicity of Solanum lycocarpum in the reproductive system of male mice and rats.

Powdered Solanum lycocarpum fruit is commonly used to treat diabetes, but apparently no studies have been conducted to evaluate potential adverse side effects. In the present paper the toxic effect of S. lycocarpum was evaluated in adult male Wistar rats and Swiss mice. The administration of an aqueous extract prepared using a powder obtained from the S. lycocarpum fruit at two different dose levels (60 mg/15 ml and 120 mg/15 ml distilled water for rats and 30 mg/15 ml and 60 mg/15 ml distilled water for mice, twice daily for 5 days in each case) did not produce body weight variations in either species although a significant weight change was observed in some organs. Significant weight loss was observed only in the ventral prostate of mice receiving the high dose treatment. These results suggest a toxic effect of S. lycocarpum on the male reproductive system of the Swiss mouse, with possible antiandrogenic activity, but there was no apparent antifertility activity in rats at the doses given.

Toxic effect of Solanum Lycocarpum in the male Wistar rats and swiss mice reproductive organs

Uma suspensäo de Solanum Lycocarpum foi administrada a ratos Wistar e camundongos suiços adultos em duas doses diferentes (60 mg/15ml e 120 mg/15ml de água destilada para ratos e 30 mg/15ml e 60 mg/15ml de água destilada para camundongos) para avaliar seu efeito no peso corporal, de testículos, de epidídimo esquerdo, de glândulas sexuais acessórias, de hipófise e na concentraçäo de espermatozóides. O extrato foi administrado duas vezes ao dia durante 5 dias, com sacrifício dos animais 3 dias após o término do tratamento. Os resultados indicaram que, a princípio, Solanum Lycocarpum näo tem efeito tóxico no rato Wistar adulto mas causou perda significativa de peso corporal, de próstata ventral, vesícula seminal e hipófise de camundongo suiço adulto. A reduçäo de peso de hipófise poderia estar indicando alto nível de testosterona ou ausência de estímulo para sua secreçäo. Quanto ao baixo peso de próstata ventral e vesícula seminal, mais estudos säo necessários para explicar as causas dessa reduçäo.

Evaluation in rabbits of the fetal effects of maternal ingestion of Solanum malacoxylon.

A study was performed to determine the possible toxic effects on the young of does that had been fed during the gestational period on a ration containing Solanum malacoxylon (Sm), a calcinogenic plant that contains a vitamin D3-glycoside conjugate. Experimental animals received a ration containing 0.03% or 0.04% of Sm leaves on days 6 to 30 of gestation. The levels of calcium, phosphorus and alkaline phosphatase in their sera, as well as their feed intake and body weight, were evaluated weekly. The does were euthanized 3 days after parturition and paraffin sections stained with haematoxylin and eosin were prepared from their heart, lungs, kidneys and aorta for histopathological examination. The young from does in the Sm 0.03% group were euthanized 3 days after birth and biochemical and histopathological determinations were performed, as described for the does. The does in both experimental groups showed decreased feed consumption and those in the Sm 0.04% group showed lower body weights throughout their gestation. Animals treated with Sm 0.04% presented a high incidence of abortion and stillbirth. There were biochemical and histopathological alterations in both experimental groups, which were more prominent in the does in the Sm 0.04% group. Litters from does treated with Sm 0.03% showed mineralization of soft tissue and an increase in phosphorus and calcium levels. These findings indicate that the vitamin D3-glycoside passes through the placental barrier to the fetus.

Avaliaçäo do potencial tóxico de extrato aquoso de Solanum lycocarpum (St. Hil) após administraçäo em camundongos suiços / Evaluation of the toxic potential of the aqueous extract of Solanum lycocarpum (St. Hil) administered to Swiss mice

The lobeira fruit (Solanum lycocarpum, St. Hil), family Solanaceae, is a globous berry which has been reported to possess sedative, diuretic, antiepileptic and antispasmodic activity. Its powder is being used as a hypoglycemic agent in Caratinga (MG). The evaluation of the lobeira toxic potential in female rats during the organogenic period showed alteration in the development of male fetuses. Owing to its popular use and the effects reported in rats, this work analyses the effect the lobeira aqueous extract, prepared with the lobeira fruit powder, in the reproductive system and different vital organs of the adult Swiss mice...

Avaliaçäo da toxidade reprodutiva de extrato aquoso de Solanum lycocarpum (St. Hil) administrado a ratos Wistar / Evaluation of the reproductive toxicity of the aqueous extract of Solanum lycocarpum (St. Hil) administered to Wistar rats

The lobeira fruit (Solanum lycocarpum, St. Hil), family Solanaceae is a plant known for its therapeutic effects - sedative, diuretic, antiepileptic and antispasmodic. Its powder is being used as a hypoglycemic agent in Caratinga (MG). The evaluation of the lobeira toxic potential in female rats during the organogenic period showed alteration in the development of male fetuses.Owing to its popular use and the effects reported above, this work analyses the effect the lobeira aqueous extract, prepared with the lobeira fruit powder, in the reproductive system and different vital organs of the adult Wistar rats...