steviol and Neoplasms

Stevia rebaudiana Bertoni is a sweet and nutrient-rich plant belonging to the Asteraceae family. Stevia leaves contain steviol glycosides including stevioside, rebaudioside (A to F), steviolbioside, and isosteviol, which are responsible for the plant's sweet taste, and have commercial value all over the world as a sugar substitute in foods, beverages and medicines. Among the various steviol glycosides, stevioside, rebaudioside A and rebaudioside C are the major metabolites and these compounds are on average 250-300 times sweeter than sucrose. Steviol is the final product of Stevia metabolism. The metabolized components essentially leave the body and there is no accumulation. Beyond their value as sweeteners, Stevia and its glycosdies possess therapeutic effects against several diseases such as cancer, diabetes mellitus, hypertension, inflammation, cystic fibrosis, obesity and tooth decay. Studies have shown that steviol glycosides found in Stevia are not teratogenic, mutagenic or carcinogenic and cause no acute and subacute toxicity. The present review provides a summary on the biological and pharmacological properties of steviol glycosides that might be relevant for the treatment of human diseases.

Topics: Cystic Fibrosis; Dental Caries; Diabetes Mellitus; Diterpenes, Kaurane; Glycosides; Humans; Hypertension; Inflammation; Neoplasms; Obesity; Plant Extracts; Stevia

Steviol glycosides, the active sweet components of stevia plant, have been recently found to possess a number of therapeutic properties, including some recorded anticancer ones against various cancer cell types (breast, ovarian, cervical, pancreatic, and colon cancer). Our aim was to investigate this anticancer potential on the two most commonly used breast cancer cell lines which differ in the phenotype and estrogen receptor (ER) status: the low metastatic, ERα+ MCF-7 and the highly metastatic, ERα-/ERβ+ MDA-MB-231. Specifically, glycosides' effect was studied on cancer cells': (a) viability, (b) functionality (proliferation, migration, and adhesion), and (c) gene expression (mRNA level) of crucial molecules implicated in cancer's pathophysiology. Results showed that steviol glycosides induced cell death in both cell lines, in the first 24 hr, which was in line with the antiapoptotic BCL2 decrease. However, cells that managed to survive showcased diametrically opposite behavior. The low metastatic ERα+ MCF-7 cells acquired an aggressive phenotype, depicted by the upregulation of all receptors and co-receptors (ESR, PGR, AR, GPER1, EGFR, IGF1R, CD44, SDC2, and SDC4), as well as VIM and MMP14. On the contrary, the highly metastatic ERα-/ERβ+ MDA-MB-231 cells became less aggressive as pointed out by the respective downregulation of EGFR, IGF1R, CD44, and SDC2. Changes observed in gene expression were compatible with altered cell functions. Glycosides increased MCF-7 cells migration and adhesion, but reduced MDA-MB-231 cells migratory and metastatic potential. In conclusion, the above data clearly demonstrate that steviol glycosides have different effects on breast cancer cells according to their ER status, suggesting that steviol glycosides might be examined for their potential anticancer activity against breast cancer, especially triple negative breast cancer (TNBC).

Topics: Diterpenes, Kaurane; ErbB Receptors; Estrogen Receptor alpha; Estrogen Receptor beta; Glucosides; Glycosides; Matrix Metalloproteinase 14; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Receptors, Estrogen; RNA, Messenger

The use of steviol glycosides as non-caloric sweeteners has proven to be beneficial for patients with type 2 diabetes mellitus (T2D), obesity, and metabolic syndrome. However, recent data demonstrate that steviol and stevioside might act as glucocorticoid receptor (GR) agonists and thus correlate with adverse effects on metabolism. Herein, we evaluated the impact of steviol, steviol glycosides, and a Greek-derived stevia extract on a number of key steps of GR signaling cascade in peripheral blood mononuclear cells (PBMCs) and in Jurkat leukemia cells. Our results revealed that none of the tested compounds altered the expression of primary GR-target genes (GILZ, FKPB5), GR protein levels or GR subcellular localization in PBMCs; those compounds increased GILZ and FKPB5 mRNA levels as well as GRE-mediated luciferase activity, inducing in parallel GR nuclear translocation in Jurkat cells. The GR-modulatory activity demonstrated by stevia-compounds in Jurkat cells but not in PBMCs may be due to a cell-type specific effect.

Topics: Adrenocorticotropic Hormone; Cell Nucleus; Cell Survival; Dexamethasone; Diterpenes, Kaurane; Gene Expression Regulation; Glucosides; Humans; Hydrocortisone; Jurkat Cells; Leukocytes, Mononuclear; Luciferases; Neoplasms; Plant Extracts; Receptors, Glucocorticoid; Response Elements; RNA, Messenger; Signal Transduction; Stevia; Tacrolimus Binding Proteins; Transcription Factors

Seventeen steviol derivatives, i.e., 2-18, and 19 isosteviol derivatives, i.e., 19-37, were prepared from a diterpenoid glycoside, stevioside (1). Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, nine steviol derivatives, i.e., 5-9 and 11-14, and five isosteviol derivatives, i.e., 28-32, exhibited activities with single-digit micromolar IC(50) values against one or more cell lines. All of these active compounds possess C(19)-O-acyl group, and among which, ent-kaur-16-ene-13,19-diol 19-O-4',4',4'-trifluorocrotonate (14) exhibited potent cytotoxicities against four cell lines with IC(50) values in the range of 1.2-4.1 μM. Compound 14 induced typical apoptotic cell death in HL60 cells upon evaluation of the apoptosis-inducing activity by flow-cytometric analysis. These results suggested that acylation of the 19-OH group of kaurane- and beyerane-type diterpenoids might be useful for enhancement of their cytotoxicities with apoptosis-inducing activity.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Survival; Diterpenes, Kaurane; Humans; Neoplasms; Stevia

The structure of exo-methylene cyclopentanone, which exists in nature tetracyclic diterpenoids products, has been proved to be an innate group for the treatment of cancer and inflammation. In this letter, four different scaffolds of tetracyclic diterpenoids including the structure exo-methylene cyclopentanone were synthesized from steviol and isosteviol and evaluated in vitro for their antitumor activity against three human cancer lines. Compounds 1a, 1b, 2b and 3b showed significant cytotoxicity, particularly, tetracyclic diterpenoids 2b, 3b were identified as the most potent and selective anticancer agents superior to adriamycin with IC(50) values of 0.9 μM and 1.5 μM, against Hep-G2 and MDA-MB-231 cell lines, respectively.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cyclopentanes; Diterpenes; Diterpenes, Kaurane; Drug Screening Assays, Antitumor; Humans; Neoplasms