Search Results (21)

Bladder cancer has a high incidence worldwide and is characterized by a high recurrence rate, metastatic potential, and a significant socioeconomic burden. Conventional treatment modalities usually exhibit serious adverse complications, which also negatively affect patients’ quality of life. In the context of exploring new treatment approaches with fewer side effects, the utilization of natural compounds as alternative and/or complementary therapeutic options seems appealing. In the present study, the potential use and effects of various bioactive phytochemicals, including curcumin, resveratrol, epigallocatechin, genistein, and several others, in bladder cancer treatment are thoroughly reviewed. A special focus is given to their potential to beneficially modulate important molecular signaling pathways and mechanisms affecting cell survival, proliferation, migration, and apoptosis, which play a crucial role in the pathogenesis of bladder cancer, such as the PI3K/AKT/mTOR, Ras/Raf/MEK/MAPK, Wnt/β-Catenin, Notch, Hedgehog, Hippo, JAK2/STAT3, and PAF/PAF-receptor pathways. Nevertheless, most studies have been conducted in cell cultures and animal models. Due to differences in genetics and metabolism, more clinical trials are needed to ensure the bio-efficacy of these phytochemicals in humans. Full article

Pioglitazone (ACTOS) is a thiazolidinedione for peroxisome proliferator-activated receptor γ (PPAR-γ) that has been well established for the second or third line treatment of type 2 diabetes mellitus. Beyond the effects on glucose metabolism, pioglitazone displays positive effects on lipid metabolism, blood pressure, endothelial function, bone density, and apoptosis of cancer cells. In fact, according to in vitro experiments and preclinical studies, PPAR-γ ligand is currently considered a potential target for both chemoprevention and cancer therapy. PPAR-γ ligands are known to inhibit cancer cell proliferation and metastasis through terminal differentiation and underexpression of inflammatory mediators. Despite its anticancer properties, pioglitazone was withdrawn by the national medicine agencies of France and Germany, due to reports of increased incidence of bladder cancer. These reports were associated with European populations undergoing higher doses and longer durations of treatment. In this review, we discuss the pharmacokinetics, therapeutic potential, and limitations regarding the clinical use of pioglitazone, with a focus on cancer treatment. Full article

Background: SHR-5 has been used as an “adaptogen” for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts’ action. Full article

Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we show that dietary feeding of kawain (a major active component in kava root extracts) to mice either before or after hydroxy butyl(butyl) nitrosamine (OH-BBN) carcinogen exposure slows down urinary bladder carcinogenesis and prolongs the survival of the OH-BBN-exposed mice. OH-BBN-induced bladder tumors exhibit significantly increased expression of lysine-specific demethylase 1 (LSD1), accompanied by decreased levels of H3K4 mono-methylation compared to normal bladder epithelium, whereas dietary kawain reverses the effects of OH-BBN on H3K4 mono-methylation. Human bladder cancer tumor tissues at different pathological grades also show significantly increased expression of LSD1 and decreased levels of H3K4 mono-methylation compared to normal urothelium. In addition, kava root extracts and the kavalactones kawain and methysticin all increase the levels of H3K4 mono- and di-methylation, leading to inhibitory effects on cell migration. Taken together, our results suggest that modification of histone lysine methylation may represent a new approach to bladder cancer prevention and treatment and that kavalactones may be promising agents for bladder cancer interception in both current and former smokers. Full article

UPII-mutant Ha-ras transgenic mice develop urothelial hyperplasia and low-grade papillary carcinoma, which mimics human non-muscle invasive bladder cancer (NMIBC). We investigated the effects and mechanisms of kawain, a main kavalactone in the kava plant, on oncogenic Ha-ras-driven urothelial carcinoma in these mice. The mice were fed at six weeks of age with vehicle control or kawain (6 g/kg) formulated food for approximately five months. Seventy-eight percent of the mice or more fed with kawain food survived more than six months of age, whereas only 32% control food-fed male mice survived, (p = 0.0082). The mean wet bladder weights (a surrogate for tumor burden) of UPII-mutant Ha-ras transgenic mice with kawain diet was decreased by approximately 56% compared to those fed with the control diet (p = 0.035). The kawain diet also significantly reduced the occurrence of hydronephrosis and hematuria in UPII-mutant Ha-ras transgenic mice. Histological examination and immunohistochemistry analysis revealed that vehicle control-treated mice displayed more urothelial carcinoma and Ki67-positive cells in the bladder compared to kawain treated mice. Global metabolic profiling of bladder tumor samples from mice fed with kawain food showed significantly more enrichment of serotonin and less abundance of xylulose, prostaglandin A2, D2 and E2 compared to those from control diet-fed mice, suggesting decreased shunting of glucose to the pentose phosphate pathway (PPP) and reduced inflammation. In addition, kawain selectively inhibited the growth of human bladder cancer cell lines with a significant suppression of 4E-BP1 expression and rpS6 phosphorylation. These observations indicate a potential impact of kawain consumption on bladder cancer prevention by rewiring the metabolic programs of the tumor cells. Full article

Pomegranate (Punica granatum L.) fruit demonstrates the repressive effectiveness of many tumors. Our previous studies showed that the PEP (pomegranate peel extract) E2 fraction obtained from the ethyl acetate layer of the pomegranate peel’s ethanol extract exhibited the highest inhibitory activities to induce Urinary bladder urothelial carcinoma (UBUC) cell apoptosis. The ethyl acetate layer could lower the volume and weight of T24 tumors and initiate apoptosis in nude mice xenografted bladder tumors. In this study, we intended to clarify the inhibitory molecular process of Taiwanese local pomegranate peel to urinary bladder urothelial carcinoma using a proteomics strategy. Gel-based proteomics (two-dimensional gel electrophoresis coupled with tandem mass spectrometry) was used to get an insight into the molecular mechanisms initiated by PEPE2 to evoke bladder cancer cell apoptosis. We found eleven down-regulated and eight up-regulated proteins in PEPE2-treated T24 cells. Our results implied that these PEPE2-dysregulated proteins belong to cell apoptosis, cell proliferation, death receptor signaling, JAK/STAT signaling, the PPAR pathway, the PPARα/RXR α pathway, Rho family GTPase signaling, and RhoGDI signaling. In addition, HSP90 and PTP1B proteins, associated with apoptosis, were de-regulated in xenografted bladder tumors in nude mice fed with an ethyl acetate layer of ethanol extract. The findings above implied that pomegranate might be a potential chemopreventive resource for UBUC carcinogenesis. Full article

Kava (Piper methysticum) has been widely consumed for many years in the South Pacific Islands and displays psychoactive properties, especially soothing and calming effects. This plant has been used in Western countries as a natural anxiolytic in recent decades. Kava has also been used to treat symptoms associated with depression, menopause, insomnia, and convulsions, among others. Along with its putative beneficial health effects, kava has been associated with liver injury and other toxic effects, including skin toxicity in heavy consumers, possibly related to its metabolic profile or interference in the metabolism of other xenobiotics. Kava extracts and kavalactones generally displayed negative results in genetic toxicology assays although there is sufficient evidence for carcinogenicity in experimental animals, most likely through a non-genotoxic mode of action. Nevertheless, the chemotherapeutic/chemopreventive potential of kava against cancer has also been suggested. Both in vitro and in vivo studies have evaluated the effects of flavokavains, kavalactones and/or kava extracts in different cancer models, showing the induction of apoptosis, cell cycle arrest and other antiproliferative effects in several types of cancer, including breast, prostate, bladder, and lung. Overall, in this scoping review, several aspects of kava efficacy and safety are discussed and some pertinent issues related to kava consumption are identified. Full article

Non-muscle-invasive bladder cancer (NMIBC) has one of the highest recurrence rates among all solid cancers and the highest lifetime treatment cost per patient. Therefore, the development of chemoprevention strategies for reducing the occurrence and recurrence of NMIBC as well as its burdens on the healthcare system is valuable. Our aim was to determine whether flavokawain A (FKA), a kava chalcone isolated from the kava plant, can target the in vivo activated Ha-ras pathway for prevention and treatment of NMIBC. UPII-mutant Ha-ras transgenic mice that develop papillary urothelial cell carcinoma were fed orally with vehicle control or FKA-formulated food for 6 months starting at 6 weeks of age. Seventy-nine percent (15/19) of male mice fed with 6 g FKA per kilogram (kg) of food survived beyond the 6 months of treatment, while 31.6% (6/19) of control food-fed male mice survived the 6-month treatment period (p = 0.02). The mean bladder weights in FKA vs. control food-fed mice were 0.216 ± 0.033 vs. 0.342 ± 0.039 g in male mice (p = 0.0413) and 0.043 ± 0.004 vs. 0.073 ± 0.004 g in female mice (p < 0.0001); FKA reduced bladder weight by 37% and 41%, respectively. The tumor burdens, determined by the wet bladder weight, in these mice were inversely related to plasma FKA concentrations. In addition to decreased bladder weight, FKA treatment significantly reduced the incidences of hydronephrosis and hematuria. FKA-treated mice exhibited more well-differentiated tumors in the bladder and ureter. Immunohistochemical analysis of FKA-treated tumors compared to those in the control group revealed fewer Ki-67- and survivin-positive cells and an increased number of p27- and TUNEL-positive cells, indicating that FKA inhibits proliferation and induces apoptosis. Overall, the results suggest that FKA can target the in vivo activated Ha-ras pathway for the prevention and treatment of NMIBC. Full article

The number of cancer cases worldwide keeps growing unstoppably, despite the undeniable advances achieved by basic research and clinical practice. Urologic tumors, including some as prevalent as prostate, bladder or kidney tumors, are no exceptions to this rule. Moreover, the fact that many of these tumors are detected in early stages lengthens the duration of their treatment, with a significant increase in health care costs. In this scenario, prevention offers the most cost-effective long-term strategy for the global control of these diseases. Although specialized diets are not the only way to decrease the chances to develop cancer, epidemiological evidence support the role of certain plant-derived foods in the prevention of urologic cancer. In many cases, these plants are rich in antiangiogenic phytochemicals, which could be responsible for their protective or angiopreventive properties. Angiogenesis inhibition may contribute to slow down the progression of the tumor at very different stages and, for this reason, angiopreventive strategies could be implemented at different levels of chemoprevention, depending on the targeted population. In this review, epidemiological evidence supporting the role of certain plant-derived foods in urologic cancer prevention are presented, with particular emphasis on their content in bioactive phytochemicals that could be used in the angioprevention of cancer. Full article

Background: Bladder cancer (urothelial cancer of the bladder) is the most common malignancy affecting the urinary system with an increasing incidence and mortality. Mouse models of bladder cancer should possess a high value of reproducibility, predictability, and translatability to allow mechanistic, chemo-preventive, and therapeutic studies that can be furthered into human clinical trials. Objectives: To provide an overview and resources on the origin, molecular and pathological characteristics of commonly used animal models in bladder cancer. Methods: A PubMed and Web of Science search was performed for relevant articles published between 1980 and 2021 using words such as: “bladder” and/or “urothelial carcinoma” and animal models. Animal models of bladder cancer can be categorized as autochthonous (spontaneous) and non-autochthonous (transplantable). The first are either chemically induced models or genetically engineered models. The transplantable models can be further subclassified as syngeneic (murine bladder cancer cells implanted into immunocompetent or transgenic mice) and xenografts (human bladder cancer cells implanted into immune-deficient mice). These models can be further divided—based on the site of the tumor—as orthotopic (tumor growth occurs within the bladder) and heterotopic (tumor growth occurs outside of the bladder). Full article

Sulforaphane (SFN), an isothiocyanate (ITCs) derived from glucosinolate that is found in cruciferous vegetables, has been reported to exert a promising anticancer effect in a substantial amount of scientific research. However, epidemical studies showed inconsistencies between cruciferous vegetable intake and bladder cancer risk. In this study, human bladder cancer T24 cells were used as in vitro model for revealing the inhibitory effect and its potential mechanism of SFN on cell growth. Here, a low dose of SFN (2.5 µM) was shown to promote cell proliferation (5.18–11.84%) and migration in T24 cells, whilst high doses of SFN (>10 µM) inhibited cell growth significantly. The induction effect of SFN on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression at both low (2.5 µM) and high dose (10 µM) was characterized by a bell-shaped curve. Nrf2 and glutathione (GSH) might be the underlying mechanism in the effect of SFN on T24 cell growth since Nrf2 siRNA and GSH-depleting agent L-Buthionine-sulfoximine abolished the effect of SFN on cell proliferation. In summary, the inhibitory effect of SFN on bladder cancer cell growth and migration is highly dependent on Nrf2-mediated GSH depletion and following production. These findings suggested that a higher dose of SFN is required for the prevention and treatment of bladder cancer. Full article

The chemopreventive potential of Resveratrol (RV) against bladder cancer and its mechanism of action have been widely demonstrated. The physicochemical properties of RV, particularly its high reactivity and low solubility in aqueous phase, have been limiting factors for its bioavailability and in vivo efficacy. In order to overcome these limitations, its inclusion in drug delivery systems needs to be taken into account. In particular, oil-in-water (O/W) nanoemulsions (NEs) have been considered ideal candidates for RV encapsulation. Since surfactant and oil composition can strongly influence NE features and their application field, a ternary phase diagram was constructed and evaluated to select a suitable surfactant/oil/water ratio. The selected sample was deeply characterized in terms of physical chemical features, stability, release capability and cytotoxic activity. Results showed a significant decrease in cell viability after the incubation of bladder T24 cancer cells with RV-loaded NEs, compared to free RV. The selected NE formulation was able to preserve and improve RV cytotoxic activity by a more rapid drug uptake into the cells. O/W NEs represent an effective approach to improve RV bioavailability. Full article

Sulforaphane (SFN) is a natural glucosinolate found in cruciferous vegetables that acts as a chemopreventive agent, but its mechanism of action is not clear. Due to antioxidative mechanisms being thought central in preventing cancer progression, SFN could play a role in oxidative processes. Since redox imbalance with increased levels of reactive oxygen species (ROS) is involved in the initiation and progression of bladder cancer, this mechanism might be involved when chemoresistance occurs. This review summarizes current understanding regarding the influence of SFN on ROS and ROS-related pathways and appraises a possible role of SFN in bladder cancer treatment. Full article

Bladder cancer (BC) is the tenth most common cancer worldwide with a high recurrence rate, morbidity and mortality. Therefore, chemoprevention and improved treatment of BC are of paramount importance. Epidemiological studies suggest that adequate vitamin A intake may be associated with reduced BC risk. In addition, retinoids, natural and synthetic derivatives of vitamin A, are intensively studied in cancer research due to their antioxidant properties and their ability to regulate cell growth, differentiation, and apoptosis. Findings from in vivo and in vitro models of BC show great potential for the use of retinoids in the chemoprevention and treatment of BC. However, translation to the clinical practice is limited. In this narrative review we discuss: (i) vitamin A and retinoid metabolism and retinoic acid signalling, (ii) the pathobiology of BC and the need for chemoprevention, (iii) the epidemiological evidence for the role of dietary vitamin A in BC, (iv) mechanistic insights obtained from in vivo and in vitro models, (v) clinical trials of retinoids and the limitations of retinoid use, (vi) novel systems of retinoid delivery, and (vii) components of retinoid signalling pathways as potential novel therapeutic targets. Full article

Although the therapeutic armamentarium for bladder cancer has considerably widened in the last few years, severe side effects and the development of resistance hamper long-term treatment success. Thus, patients turn to natural plant products as alternative or complementary therapeutic options. One of these is curcumin, the principal component of Curcuma longa that has shown chemopreventive effects in experimental cancer models. Clinical and preclinical studies point to its role as a chemosensitizer, and it has been shown to protect organs from toxicity induced by chemotherapy. These properties indicate that curcumin could hold promise as a candidate for additive cancer treatment. This review evaluates the relevance of curcumin as an integral part of therapy for bladder cancer. Full article