Chondroitin sulphate enhances the antitumor activity of gemcitabine and mitomycin-C in bladder cancer cells with different mechanisms

Abstract

Abstract. Non-muscle invasive bladder cancer is the most common type of bladder cancer in Western countries. The glycosaminoglycan (GAG) layer at the bladder surface non-specifically blocks the adherence of bacteria, ions and molecules to the bladder epithelium and bladder cancer cells express CD44 that binds GAG. Currently, there are few options other than cystectomy for the management of non-muscle invasive bladder cancer with intravesical chemotherapy using several drugs such as gemcitabine (GEM) and mitomycin-C (MMC) with poor prophylactic activity. In this study, we investigated the effects of the GAG chondroitin sulphate (CS) on the growth inhibition of human bladder cancer cell lines HT-1376 and effects of the combination between GEM or MMC with CS. We have found that CS, MMC and GEM induced 50% growth inhibition at 72 h. Therefore, we have evaluated the growth inhibition induced by different concentration of CS in combination with MMC or GEM, respectively, at 72 h. We have observed, at Calcusyn analysis, a synergism when HT-1376 cells were treated with CS in combination with MMC or GEM, respectively, if used at an equimolar ratio. We have also found that CS/GEM combination induced a strong potentiation of apoptosis with the consequent activation of caspases 9 and 3. On the other hand, HT-1376 cells were necrotic if exposed to the CS/MMC combination and no signs of caspase activation was observed.In conclusion, in the human bladder cancer cell line HT-1376 pharmacological combination of CS with GEM or MMC resulted in a strong synergism on cell growth inhibition. IntroductionNon-muscle invasive bladder cancer is the most common type of bladder cancer in Western countries. There are multiple risk factors for bladder cancer, which include exposure to tobacco and industrial chemicals, ingestion of arsenic-laced water, radiation therapy to organs adjacent to the bladder, therapeutic use of alkylating agents in chemotherapy regimens, and infection with the trematode Schistosoma haematobium. The glycosaminoglycan layer at the bladder surface non-specifically blocks the adherence of bacteria, ions and molecules to the epithelium. Therefore, it may be an important element in the first line of defence against infection, calculi and even carcinogens for the transitional cells of the bladder. Qualitative or quantitative defects in the glycosaminoglycan(s) expression may influence an individual's susceptibility to the development of bladder tumors (1-3).At initial presentation 70% of bladder cancers are superficial and include carcinoma in situ (CIS), Ta, and T1 disease. Transurethral resection (TUR) is the primary mode of clinical management for both diagnosis and treatment of superficial bladder cancer, but 60 to 70% of these cancers recur and 20% progress to a higher stage (4). TUR is commonly followed by intravesical infusion of either chemotherapy or immune-modulating agents in order to reduce the incidence of recurrence and progression. Bacille Calmette-Guèrin (BCG) is the most effective agent in the prevention ...

Description of a Novel Probiotic Concept: Implications for the Modulation of the Immune System

“…Thus, although chondroitin sulfate has been used for decades as a dietary supplement and a symptomatic slow acting drug, only recently it has been demonstrated that it is readily degraded and fermented in vitro by human gut microbes, suggesting that it may act as a prebiotic (Shang et al, 2016). In addition, it is well acknowledged that chondroitin sulfate negatively regulates cancer cell signaling (Willis and Klüppel, 2014) and enhances the activity of conventional chemotherapeutics (Ferro et al, 2012), a finding that is consistent with the observation that sulfated motifs of chondroitin sulfate inhibit triple negative breast cancer (Poh et al, 2015). In a peculiar synergism with Kluyveromyces marxianus, chondroitin sulfate inhibits inflammation (Vallières and du Souich, 2010) and is endowed with immune-stimulating properties consisting in the activation of macrophages without inducing the production of pro-inflammatory cytokines (Wrenshall et al, 1999).…”

Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

“…Members of the CHST family also mediate inflammation, immunity, angiogenesis, and extracellular matrix reorganization 63,64. So far there is one study 65 that reports the involvement of chondroitin sulfates in enhancing antitumor activity of gemcitabine in human bladder cancer cells.…”

The biology and role of CD44 in cancer progression: therapeutic implications

“…CS is a ligand for CD44 [ 43 ] and it protects chronic lymphocytic leukemia (CLL) cells from apoptosis [ 45 ]. Combination of CS with gemcitabine strongly inhibited human bladder cancer cells growth [ 46 ]. CS-g-poly copolymers can be self-assembled into micelles in water and then used to encapsulate camptothecin.…”