A Potent Chemotherapeutic Strategy with Eg5 Inhibitor against Gemcitabine Resistant Bladder Cancer

• Published in: PloS one 2015-12, Vol.10 (12), p.e0144484-e0144484
• Main Authors: Sun, Liang, Lu, Jiaju, Niu, Zhihong, Ding, Kejia, Bi, Dongbin, Liu, Shuai, Li, Jiamei, Wu, Fei, Zhang, Hui, Zhao, Zuohui, Ding, Sentai
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Apoptosis - drug effects; Apoptosis - genetics; Binding sites; Biotechnology; Bladder; Bladder cancer; Cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Chemotherapy; Cluster Analysis; Cysteine - analogs & derivatives; Cysteine - pharmacology; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Development and progression; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug therapy; Enzyme inhibitors; Enzymes; Ethics; Female; Gemcitabine; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Inhibitors; Kinesin - antagonists & inhibitors; Kinesin - genetics; Kinesin - metabolism; Laboratory animals; Medical prognosis; Metastasis; Methods; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Ovarian cancer; Pancreatic cancer; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoside Diphosphate Reductase - adverse effects; Ribonucleoside Diphosphate Reductase - genetics; Ribonucleoside Diphosphate Reductase - metabolism; Ribonucleotide reductase; RNA Interference; Studies; Target recognition; Trityl Compounds - pharmacology; Tumor Burden - drug effects; Tumor Burden - genetics; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; Urinary bladder; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urology; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0144484

Development of resistance to gemcitabine is a major concern in bladder cancer therapy, and the mechanism remains unclear. Eg5 has been recently identified as an attractive target in cancer chemotherapy, so novel targeted chemotherapy with Eg5 inhibitor is expected to improve the anticancer effect in gemcitabine-resistant bladder cancer. In this research, RT112-Gr cells were 350-fold less sensitive to gemcitabine than the parental cell lines, while KU7-Gr cells were 15-fold less sensitive to gemcitabine than the parental cell lines. Human OneArray Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in RT112 and RT112-Gr cells. The anti-proliferative activity of S(MeO)TLC, an Eg5 inhibitor, was analyzed in RT112-Gr cell lines using a cell viability assay. Furthermore, the inhibitory effect was evaluated in vivo using subcutaneous xenograft tumor model. According to the result of Human OneArray GeneChip, RRM1 and RRM2 were up-regulated, while there was no significant change in Eg5. Trypan blue staining confirmed that in S(MeO)TLC and Gemcitabine combining S(MeO)TLC group cell viability were significantly decreased in RT112-Gr cells as compared with other groups. S(MeO)TLC and S(MeO)TLC+gemcitabine groups prominently suppressed tumor growth in comparison with other groups' in vivo. There were no significant differences in S(MeO)TLC and gemcitabine+S(MeO)TLC group in the effect of inhibition of bladder cancer in vivo and in vitro. Our data collectively demonstrated that S(MeO)TLC represents a novel strategy for the treatment of gemcitabine resistant bladder cancer.