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

Non-muscle invasive bladder cancer is the most common type of bladder cancerin Western countries. The glycosaminoglycan (GAG) layer at the bladder surfacenon-specifically blocks the adherence of bacteria, ions and molecules to the bladderepithelium and bladder cancer cells express CD44 that binds GAG. Currently, thereare few options other than cystectomy for the management of non-muscle invasivebladder cancer with intravesical chemotherapy using several drugs such as gemcitabine(GEM) and mitomycin-C (MMC) with poor prophylactic activity. In this study, weinvestigated the effects of the GAG chondroitin sulphate (CS) on the growth inhibitionof human bladder cancer cell lines HT-1376 and effects of the combination betweenGEM or MMC with CS. We have found that CS, MMC and GEM induced 50% growth inhibitionat 72 h. Therefore, we have evaluated the growth inhibition induced by differentconcentration of CS in combination with MMC or GEM, respectively, at 72 h. Wehave observed, at Calcusyn analysis, a synergism when HT-1376 cells were treatedwith CS in combination with MMC or GEM, respectively, if used at an equimolarratio. We have also found that CS/GEM combination induced a strong potentiationof apoptosis with the consequent activation of caspases 9 and 3. On the otherhand, HT-1376 cells were necrotic if exposed to the CS/MMC combination and nosigns of caspase activation was observed. In conclusion, in the human bladdercancer cell line HT-1376 pharmacological combination of CS with GEM or MMC resultedin a strong synergism on cell growth inhibition.