cytellin and Prostatic-Neoplasms

Cancer is one of the primary causes of death worldwide, and its incidence continues to increase yearly. Despite significant advances in research, the search for effective and nontoxic preventive and therapeutic agents remains greatly important. Cancer is a multimodal disease, where various mechanisms play significant roles in its occurrence and progression. This highlights the need for multitargeted approaches that are not only safe and inexpensive but also provide effective alternatives for current therapeutic regimens. β-Sitosterol (SIT), the most abundant phytosterol found in various plant foods, represents such an option. Preclinical evidence over the past few decades has overwhelmingly shown that SIT exhibits multiple anticancer activities against varied cancers, such as liver, cervical, colon, stomach, breast, lung, pancreatic, and prostate cancers, in addition to leukemia, multiple myeloma, melanoma, and fibrosarcoma. In this article, we present the latest advances and perspectives on SIT-systematically summarizing its antitumor mechanisms of action into 7 main sections and combining current challenges and prospects-for its use as a promising agent for cancer prevention and treatment. In particular, SIT plays a role in cancer prevention and treatment mainly by enhancing apoptosis, inducing cell cycle arrest, bidirectionally regulating oxidative stress, improving metabolic reprogramming, inhibiting invasion and metastasis, modulating immunity and inflammation, and combating drug resistance. Although SIT holds such great promise, the poor aqueous solubility and bioavailability coupled with low targeting efficacy limit its therapeutic efficacy and clinical application. Further research on novel drug delivery systems may improve these deficiencies. Overall, through complex and pleiotropic mechanisms, SIT has good potential for tumor chemoprevention and chemotherapy. However, no clinical trials have yet proven this potential. This review provides theoretical basis and rationality for the further design and conduct of clinical trials to confirm the anticancer activity of SIT.

Topics: Antineoplastic Agents; Chemoprevention; Humans; Male; Prostatic Neoplasms; Sitosterols

All the currently available cancer therapeutic options are expensive but none of them are safe. However, traditional plant-derived medicines or compounds are relatively safe. One widely known such compound is beta-sitosterol (BS), a plant derived nutrient with anticancer properties against breast cancer, prostate cancer, colon cancer, lung cancer, stomach cancer, ovarian cancer, and leukemia. Studies have shown that BS interfere with multiple cell signaling pathways, including cell cycle, apoptosis, proliferation, survival, invasion, angiogenesis, metastasis and inflammation. Most of the studies are incomplete partly due to the fact that BS is relatively less potent. But the fact that it is generally considered as nontoxic, the opposite of all currently available cancer chemo-therapeutics, is missed by almost all research communities. To offset the lower efficacy of BS, designing BS delivery for "cancer cell specific" therapy hold huge potential. Delivery of BS through liposome is one of such demonstrations that has shown to be highly promising. But further research did not progress neither in the field of drug delivery of BS nor in the field on how BS mediated anticancer activities could be improved, thus making BS an orphan nutraceutical. Therefore, extensive research with BS as potent anticancer nutraceutical is highly recommended.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Colonic Neoplasms; Dietary Supplements; Drug Delivery Systems; Female; Humans; Leukemia; Liposomes; Lung Neoplasms; Male; Neoplasms; Orphan Drug Production; Phytoestrogens; Prostatic Neoplasms; Signal Transduction; Sitosterols

Topics: Double-Blind Method; Drug Tolerance; Humans; Liver; Liver Diseases; Male; Plants, Medicinal; Prostatic Neoplasms; Sitosterols

Crateva adansonii DC (Capparaceae) is a shrub used to treat tumors in Cameroon. In our previous reports, a Crateva adansonii dichloromethane-methanol (DCM/MeOH) extract was shown to prevent chemically induced tumors in Wistar rats.. To determine the bioactive principle of Crateva adansonii extract and to elucidate its underlying mechanism.. An activity-guided fractionation was realized using MTT assay. To investigate if the bioactive compound daucosterol (CA2) accounted for the previously observed anticancer effects of the C. adansonii extract, it was tested on cell growth, cell proliferation, cell cycle, cell death mechanism and cell migration. In addition, cell cycle- and apoptosis-regulating proteins were assessed by Western blotting.. Daucosterol (CA2), a steroid saponin, was identified as major anticancer principle of the C. adansonii extract. Daucosterol significantly inhibited LNCaP, DU145 and PC3 prostate carcinoma cell growth and proliferation at the optimal concentration of 1 μg/mL. It also significantly increased the number of late apoptotic (DU145) and apoptotic (PC3) cells. The number of cells in S phase increased in DU145, while the number of G0/G1 cells decreased. Cell cycle proteins (cdk1, pcdk1, cyclin A and B) were down-regulated in DU145 and PC3 cells, whereas only cdk2 was down-regulated in PC3 cells. Moreover, the anti-apoptotic Akt, pAKT and Bcl-2 proteins were down-regulated, while the pro-apoptotic protein Bax was up-regulated. CA2 induced anti-metastatic effects by decreasing chemotaxis and cell migration, while it increased cell adhesion to fibronectin and collagen matrix.. These results suggest that daucosterol is the major active principle responsible at least in part for the anticancer effect of the extract of Crateva adansonii.

Topics: Apoptosis; Biological Assay; Cameroon; Capparaceae; Cell Line, Tumor; Cell Proliferation; Chemical Fractionation; Chemotaxis; Down-Regulation; Drug Screening Assays, Antitumor; Humans; Male; Medicine, African Traditional; Neoplasm Invasiveness; Plant Extracts; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Sitosterols; Up-Regulation

Plant sterols (phytosterols) have been widely accepted as a natural anti-cancer agent in multiple malignant tumors. This study was designed to investigate the functions of daucosterol in prostate cancer progression and its possible molecular mechanisms. Our results showed that daucosterol inhibited cell proliferation and induced cell cycle arrest. Moreover, daucosterol treatment obviously promoted apoptosis and autophagy. An autophagy inhibitor, 3-methyladenine (3-MA) was proved to counteract daucosterol-triggered autophagy, growth inhibition, and apoptosis, indicating that daucosterol-induced apoptotic response was dependent on autophagy. Additionally, treatment with daucosterol resulted in increased phosphorylation of c-Jun N-terminal kinase (JNK). Furthermore, pre-treatment with a JNK-specific inhibitor SP600125 abated daucosterol-elicited autophagy and apoptotic cell death. Taken together, our findings demonstrated that daucosterol blocked prostate cancer growth at least partly through inducing autophagic-dependent apoptosis via activating JNK signaling, providing a promising candidate for the development of antitumor drugs in prostate cancer treatment.

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Enzyme Activation; Humans; JNK Mitogen-Activated Protein Kinases; Male; Prostatic Neoplasms; Sitosterols

Aberrant epigenetic modifications are responsible for tumor development and cancer progression; however, readily reversible. Bioactive molecules from diets are promising to cure cancer by modulating epigenetic marks and changing immune response. These compounds specifically target the activity of DNMTs and HDACs to cure various human cancers. In view of this, we investigated the anticancer and epigenetic regulatory activities of an edible-plant Paederia foetida. The efficacy of methanolic extract of P. foetida leaves (MEPL) was tested for the modulation of epigenetic factors in gene silencing, i.e. DNMT and HDAC and expression pattern of certain tumor-suppressor genes. After treatment of prostate cancer cells (PC-3 and DU-145) with MEPL, lupeol and β-sitosterol; induction of apoptosis, decrease in cellular-viability and inhibition of cellular-migration were noticed. Simultaneously there was inhibition of DNMT1, HDACs and pro-inflammatory, IL-6, IL1-β, TNF-α and anti-inflammatory, IL-10 genes in cancer and THP1 cell lines. The DNMT1 protein content, enzyme activity and Bcl2 expression decreased significantly; however, expression of E-cadherin (CDH1) and pro-apoptotic gene Bax increased significantly after the treatment of cells with drugs. We conclude plant-derived compounds can be considered to target epigenetic machineries involved with malignant transformation and can open new avenues for cancer therapeutics provoking immune response.

Topics: Cell Line, Tumor; Cell Survival; DNA (Cytosine-5-)-Methyltransferase 1; Gene Expression Regulation, Neoplastic; Histone Deacetylase 1; Histone Deacetylase 2; Humans; Inflammation; Male; Pentacyclic Triterpenes; Phytochemicals; Plant Extracts; Plant Leaves; Prostatic Neoplasms; RNA, Messenger; Rubiaceae; Sitosterols

Arum palaestinum is a plant commonly found in the Middle East that is ingested as an herbal remedy to fight cancer. However, no studies have examined the direct effect of the plant/plant extract on tumor growth in an animal model.. Verified prostate cancer cells were plated as 3D spheroids to determine the effect of extract from boiled Arum Palaestinum Boiss roots. In addition, male NU/NU mice (8 weeks old) with xenograft tumors derived from the prostate cancer cell line were treated daily with 1000 mg/kg body weight gavage of the suspension GZ17. The tumor growth was measured repeatedly with calipers and the excised tumors were weighed at the termination of the 3 week study. Control mice (10 mice in each group) received vehicle in the same manner and volume.. The number of live prostate cancer cells declined in a dose/dependent manner with a 24 h exposure to the extract at doses of 0.015 to 6.25 mg/mL. A fortified version of the extract (referred to as GZ17) that contained higher levels of isovanillin, linolenic acid and β-sitosterol had a stronger effect on the cell death rate, shifting the percentage of dead cells from 30 % to 55 % at the highest dose while the vehicle control had no effect on cell numbers. When GZ17 was applied to non-cancer tissue, in this case, human islets, there was no cell death at doses that were toxic to treated cancer cells. Preliminary toxicity studies were conducted on rats using an up-down design, with no signs of toxic effect at the highest dose. NU/NU mice with xenograft prostate tumors treated with GZ17 had a dramatic inhibition of tumor progression, while tumors in the control group grew steadily through the 3 weeks. The rate of tumor volume increase was 73 mm(3)/day for the vehicle group and 24 mm(3)/day for the GZ17 treated mice. While there was a trend towards lower excised tumor weight at study termination in the GZ17 treatment group, there was no statistical difference.. Fortified Arum palaestinum Boiss caused a reduction in live cells within prostate cancer spheroids and blocked tumor growth in xenografted prostate tumors in mice without signs of toxicity.

Topics: alpha-Linolenic Acid; Animals; Antineoplastic Agents; Arum; Benzaldehydes; Cell Line, Tumor; Cell Proliferation; Male; Mice; Plant Extracts; Prostatic Neoplasms; Rats; Sitosterols; Spheroids, Cellular; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Saw Palmetto Berry Extract (SPBE) is applied for prostate health and treatment of urinary tract infections, nonbacterial prostitis and Benign Prostatic Hyperplasia (BPH) in man. An assumption is that SPBE affects tumor cell progression and migration in breast and prostate tissue. In this work, DU-145 cells were used to demonstrate that SPBE and its sterol components, beta-sitosterol and stigmasterol, inhibit prostate cancer growth by increasing p53 protein expression and also inhibit carcinoma development by decreasing p21 and p27 protein expression. In the presence of cholesterol, these features are not only reversed but increased significantly. The results show for the first time the potential of SPBE, beta-sitosterol and stigmasterol as potential anti-tumor agents. Since the protein p53 is also regarded as nuclear matrix protein facilitating actin cytoskeletal binding, 2D tractions were measured. The cell adhesion strength in the presence of SPBE, beta-sitosterol and cholesterol and the observation was that the increase in p53 expression triggered an increase in the intracellular force generation. The results suggest a dual function of p53 in cells.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Humans; Male; Plant Extracts; Prostatic Neoplasms; Serenoa; Sitosterols; Stigmasterol

Cocoa contains many different types of physiologically active components. It was shown that cocoa beans are rich in specific antioxidants such as flavonoids, catechins, epicatechins and proanthocyanidins. Additionally, beta-sitosterol, the most common phytosterol, may play a protective role in the development of cancer. The aim of this in-vitro study was to evaluate the inhibitory effect of different cocoa polyphenols extracts, alone or combined with beta-sitosterol, on two human prostate cancer cell lines (nonmetastatic 22Rv1 cells and metastatic DU145 cells) and a normal human prostate cell line (RWEP-1). A synergy between beta-sitosterol and cocoa polyphenols extract was also researched. Cells were treated independently with five products from 1 to 72 h: (1/) synthetic beta-sitosterol, (2/) a cocoa polyphenols extract supplemented with beta-sitosterol, (3/) three different cocoa polyphenols extracts naturally containing beta-sitosterol. In the experiment, beta-sitosterol was tested from 10(-6) to 10(-3)%; cocoa polyphenols extract supplementation was with 0.72% beta-sitosterol; finally cocoa polyphenols extracts were added to the cells at very low concentrations ranging from 0.001 to 0.2%. The growth and viability of cells were measured using colorimetric assay at 1, 3, 6, 24, 48 and 72 h of treatment. IC50 and IC100 corresponding to the concentration leading to a decrease of 50% and 100% of cell growth were determined. At the highest tested concentration, cocoa polyphenols extracts induced a complete inhibition of growth of metastatic and nonmetastatic cancer cell lines. In addition, cocoa polyphenols extracts were more active against local cancer cells than against metastatic cells. Moreover, at the highest tested concentration, cocoa polyphenols extracts are not effective on a normal prostate cell lines. Beta-sitosterol induced low growth inhibition of both cancer cell line. Cocoa polyphenols extracts, however, were significantly more active and showed a strong and fast inhibition of cell growth than beta-sitosterol alone. No synergy or addition was observed when beta-sitosterol was tested together with the cocoa polyphenols extract. Our results show that cocoa polyphenols extracts have an antiproliferative effect on prostate cancer cell growth but not on normal cells, at the highest tested concentration.

Topics: Antineoplastic Agents; Cacao; Carcinoma; Cell Proliferation; Dose-Response Relationship, Drug; Flavonoids; Humans; Male; Phenols; Polyphenols; Prostate; Prostatic Neoplasms; Sitosterols; Time Factors; Tumor Cells, Cultured

A mixture of 6-O-acyl-beta-D-glucosyl-beta-sitosterols, the acyl moeity being primarily palmitoyl and linoleyl with minor amounts of stearyl and oleyl, has been isolated as a potent cytotoxic agent from fig (Ficuscarica) latex and soybeans. Identity was established by spectroscopic methods (NMR, MS) and confirmed by chemical synthesis. Both the natural and the synthetic compounds showed in vitro inhibitory effects on proliferation of various cancer cell lines.

Topics: Antineoplastic Agents, Phytogenic; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Female; Fruit; Glucosides; Glycine max; Humans; Latex; Leukemia; Lymphoma; Magnetic Resonance Spectroscopy; Male; Mammary Neoplasms, Animal; Mass Spectrometry; Plants, Medicinal; Prostatic Neoplasms; Sitosterols; Tumor Cells, Cultured

The dietary effect of phytosterols (PS) versus cholesterol on the growth and metastasis of the PC-3 human prostate cancer cells in SCID mice was studied. Also, their direct effect on the growth and migration of these cells in vitro was analysed. In the in vivo experiment, SCID mice were fed a diet containing 2% of either PS mixture or cholesterol plus 0.2% cholic acid and implanted with 2 x 10(6) tumour cells per mouse. Tumour growth was monitored for 8 weeks post inoculation. Animals fed the PS diet had tumours 40-43% smaller than those fed the cholesterol diet. Furthermore, the number of mice with lymph node and lung metastasis was almost one-half that of the cholesterol-fed group. In the in vitro studies, both beta-sitosterol and campesterol inhibited the growth of PC-3 cells by 70% and 14%, respectively, while cholesterol supplementation increased the growth by 18% when compared with controls. PS inhibited the invasion of PC-3 cells into Matrigel-coated membranes by 78% while cholesterol increased it by 43% as compared with the cells in the control media. Migration of tumour cells through 8 microm pore membranes was reduced by 60-93% when the PC-3 cells were in PS media, as compared with a 67% increase after cholesterol supplementation. PS supplementation reduced the binding of PC-3 cells to laminin by 15-38% and fibronectin by 23% while cholesterol increased binding to type IV collagen by 36%. It was concluded that PS indirectly (in vivo as a dietary supplement) and directly (in tissue culture media) inhibited the growth and metastasis of PC-3 cells. beta-Sitosterol was more effective than campesterol in offering this protection in most of the parameters studied.

Topics: Animals; Body Weight; Cell Adhesion; Cholesterol; Humans; Male; Mice; Mice, SCID; Models, Animal; Neoplasm Metastasis; Phytosterols; Prostatic Neoplasms; Sitosterols; Tumor Cells, Cultured

Previous work from this laboratory suggests an activation of the sphingomyelin cycle as a mechanism for growth inhibition with the incorporation of beta-sitosterol (SIT) into human prostate cancer LNCaP cells. In the present study we examined two key enzymes that have been shown to play a role in the sphingomyelin cycle. Dietary sterols (SIT and cholesterol) were compared for their effect on LNCaP cell growth, phospholipase D (PLD) activity, and protein phosphatase 2A (PP 2A) activity and expression. PP 2A has been suggested as a direct in vitro target of ceramide action on cell growth and apoptosis. Ceramide also inhibits phorbol myristate acetate-stimulated PLD. SIT (16 microM) increased PP 2A activity by 50% compared with cholesterol treatment in LNCaP prostate cells; however, SIT did not alter protein levels of PP 2A. There was an increase in PLD activity in the presence of phorbol myristate acetate in cells supplemented with 16 microM SIT compared with those supplemented with cholesterol after five days of treatment. The present study suggests that the activation of PP 2A added support to the role of the activation of the sphingomyelin cycle by SIT treatment. However, the increase in PLD activity, which was modest but significant, with SIT supplementation suggests that this pathway may be modulated by other mechanisms. This includes the incorporation of SIT into cell membranes that may alter fluidity and, thus, influence the activation of membrane-bound enzymes such as PLD.

Topics: Apoptosis; Cell Division; Ceramides; Enzyme Activation; Humans; Male; Phospholipase D; Phosphoprotein Phosphatases; Prostatic Neoplasms; Protein Phosphatase 2; Sitosterols; Sphingomyelins; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Work from our laboratory, as well as others, suggests a protective role of phytosterols (PS), especially beta-sitosterol, from colon, prostate, and breast cancer. Asians and vegetarians consume higher amounts of PS than Western societies. The latter societies have a higher incidence of these cancers than Asians and vegetarians. The aim of this study was to evaluate peanuts and its products as sources of PS in the American diet. Roasted peanuts contain 61-114 mg PS/100 g depending on the peanut variety, 78-83% of which is in the form of beta-sitosterol. Unrefined peanut oil contains 207 mg PS/100 g, which is similar to that of the US Department of Agriculture Nutrient Database. This value is higher than that of unrefined olive oil. Refining these oils results in reduction in PS concentration in the oil. This loss is greater in the case of olive oil than peanut oil. Further refining, such as deodorization, results in significant loss in PS, but hydrogenation after refining has a minimal effect on PS loss. Peanut butter, which represents 50% of the peanuts consumed in the United States, contains 144-157 mg PS/100 g. Peanut flour, which results from partial removal of oil from peanuts, contains 55-60 mg PS/100 g. The data suggest that peanuts and its products, such as peanut oil, peanut butter, and peanut flour, are good sources of PS.

Topics: Antineoplastic Agents; Arachis; Breast Neoplasms; Colonic Neoplasms; Female; Humans; In Vitro Techniques; Male; Phytosterols; Phytotherapy; Prostatic Neoplasms; Sitosterols

Epidemiological evidence has shown that men consuming a low-fat, high-fiber diet containing high amounts of plant products have a lower risk of prostate cancer than men consuming a Western diet. One of the main differences between these two diets is the type of dietary fat, including dietary sterols. This study was undertaken to compare the effect of two dietary sterols on prostate cancer cells in vitro. beta-Sitosterol (SIT), the most common plant sterol, and cholesterol, an animal sterol, were compared for effect on LNCaP cell growth, differentiation, apoptosis, and sphingomyelin cycle intermediates. Cells were treated for up to seven days with sterols delivered by a cyclodextrin vehicle. Compared with cholesterol, SIT (16 microM) decreased growth by 24% and induced apoptosis fourfold, which was accompanied by cell rounding and a 50% increase in ceramide production. No effect was observed on differentiation as measured by prostate-specific antigen and prostatic acid phosphatase, although total acid phosphatase increased with SIT treatment for up to seven days. The results suggest that the decrease in cell number and increase in apoptosis associated with SIT treatment are mediated by activating the sphingomyelin cycle.

Topics: Apoptosis; Biomarkers, Tumor; Cell Differentiation; Cell Division; Cholesterol; Humans; Male; Prostatic Neoplasms; Sitosterols; Sphingomyelins; Tumor Cells, Cultured

Topics: Adenoma; Humans; Male; Prostaglandins; Prostaglandins E; Prostaglandins F; Prostatic Neoplasms; Sitosterols

Topics: Adenoma; Humans; Male; Plants, Medicinal; Prostatic Neoplasms; Sitosterols