Abstract
Objective To evaluate the antitumor effect of cyclodextrin-curcumin complex (CDC) on human and rat urothelial carcinoma cells in vitro and to evaluate the effect of intravesical instillations of CDC, BCG, and the combination in vivo in the AY-F344 orthotopic bladder cancer rat model. Curcumin has anticarcinogenic activity on urothelial carcinoma and is therefore under investigation for the treatment of non-muscle invasive bladder cancer. Curcumin and BCG share immunomodulating pathways against urothelial carcinoma. Methods Curcumin was complexed with cyclodextrin to improve solubility. Four human urothelial carcinoma cell lines and the AY-27 rat cell line were exposed to various concentrations of CDC in vitro. For the in vivo experiment, the AY-27 orthotopic bladder cancer F344 rat model was used. Rats were treated with consecutive intravesical instillations of CDC, BCG, the combination of CDC+BCG, or NaCl as control. Results CDC showed a dose-dependent antiproliferative effect on all human urothelial carcinoma cell lines tested and the rat AY-27 urothelial carcinoma cell line. Moreover, intravesical treatment with CDC and CDC+BCG results in a lower percentage of tumors (60% and 68%, respectively) compared to BCG (75%) or control (85%). This difference with placebo was not statistically significant (p=0.078 and 0.199, respectively). However, tumors present in the placebo and BCG-treated rats were generally of higher stage. Conclusions Cyclodextrin-curcumin complex showed an antiproliferative effect on human and rat urothelial carcinoma cell lines in vitro. In the aggressive orthotopic bladder cancer rat model, we observed a promising effect of CDC treatment and CDC in combination with BCG.
Highlights
New treatment options for patients with non-muscle invasive bladder cancer (NMIBC) are urgently needed
Based on tumor characteristics and other parameters, the NMIBC-patient is classified in a risk category and treated adjuvantly: in general, intermediate-risk patients receive intravesical chemotherapy whereas high-risk patients are treated with intravesical Bacillus Calmette Guerin (BCG)
Cyclodextrin-curcumin (CDC) 12 mg/ml was prepared by a pH shift method: In a 0.18 mol/L sodium hydroxide solution, 112 g/L hydroxypropyl-γ-cyclodextrin (Wacker Chemie, Munich Germany) and 15 g/L curcumin (Sabinsa Corporation, East Windsor, NJ, USA) were dissolved and the pH was adjusted to 6.0 using hydrochloric acid and citric acid
Summary
New treatment options for patients with non-muscle invasive bladder cancer (NMIBC) are urgently needed. Despite transurethral resection and adjuvant treatment with intravesical instillations, these bladder tumors recur in around onethird to two-thirds of patients, depending on risk category [1, 2]. Based on tumor characteristics and other parameters, the NMIBC-patient is classified in a risk category and treated adjuvantly: in general, intermediate-risk patients receive intravesical chemotherapy whereas high-risk patients are treated with intravesical Bacillus Calmette Guerin (BCG). Even after BCG treatment for 1-3 years, the 5-yr risk of recurrence is 41.3% [1]. There are considerable side effects ranging from mild urogenital complaints to severe systemic side effects. Due to recent BCG shortage, future alternatives for adjuvant treatment are more than welcome
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