Apoptosis-inducing effects of curcumin derivatives in human ... : Anti-Cancer Drugs (original) (raw)
PRECLINICAL REPORTS
Tong, Qiang-Songa; Zheng, Li-Duanb; Lu, Penga; Jiang, Feng-chaod; Chen, Fang-Mina; Zeng, Fu-Qinga; Wang, Lianga; Dong, Ji-Huac
Departments of aSurgery
bPathology and
cCentral Laboratory, Union Hospital of Tongji Medical College
dDepartment of Pharmaceutical Chemistry, Tongji Pharmaceutical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
Correspondence to Q.-S. Tong, Department of Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China.
Tel: +86 27 85991567; fax: +86 27 85726396;
e-mail: [email protected]
Sponsorship: Supported by the National Natural Science Foundation of China (30200284) and the Science Foundation of Huazhong University of Science and Technology.
Received 27 September 2005 Accepted 14 November 2005
Abstract
Our aim was to prepare curcumin derivatives and study their apoptosis-inducing effects on bladder cancer cells in order to establish a basis for targeted chemotherapy of cancer. _n_-Maleoyl-L-valine-curcumin (NVC) and _n_-maleoyl-glycine-curcumin (NGC) were chemically synthesized. Intracellular esterase activity of the human bladder cancer EJ cell line and renal tubular epithelial (HKC) cells was examined by 6-carboxyfluorescein diacetate fluorometry. After incubation with NVC or NGC for 6–24 h, cell viability was detected by MTT colorimetry. Cell apoptosis and apoptotic rates were measured by acridine orange/ethidium bromide staining, TUNEL labeling and flow cytometry. Intracellular caspase-3 activities were determined by spectrophotometry. The esterase activity within EJ cells was 10.2-fold higher than that of HKC cells, which was abolished by bis-_p_-nitrophenylphosphate, an esterase inhibitor, resulting in decreases in NVC- and NGC-mediated cell viability arrest. For EJ cells, the IC50 values of NVC (20.1 μmol/l) and NGC (18.7 μmol/l) were close to curcumin (16.5 μmol/l). Meanwhile, their IC50 values on HKC cells were, respectively, 4.06- and 3.23-fold higher than curcumin. Moreover, NVC and NGC induced apoptosis of EJ cells by 10.13–23.36 and 12.42–28.56%, respectively. Administration of these two derivatives resulted in decreased apoptosis of HKC cells compared with curcumin. The caspase-3 activities of EJ cells, but not of HKC cells, were 5.21- and 5.63-fold enhanced by NVC and NGC, respectively. Thus, novel esterase-sensitive curcumin derivatives were synthesized, which induced extensive apoptosis of bladder cancer EJ cells, but not normal cells.
© 2006 Lippincott Williams & Wilkins, Inc.