Anti-Tumor Activity and Mechanism of Gemcitabine Derivative SZY-200 Assembled from Gemcitabine-Lauric Acid Conjugate on Human Bladder Cancer Cells

Abstract Gemcitabine is a first-line drug for the treatment of bladder cancer. One of the most important mechanisms of gemcitabine resistance is the low expression of cellular membrane transporter hENT1. Various derivatives containing fatty acid side chains have been developed in order to facilitate gemcitabine uptake and prolong its retention in cells, such as CP-4126. In this study, the anti-tumor effect and mechanism of a new derivative of gemcitabine named SZY-200 on bladder cancer cells was investigated. SZY-200 was assembled from gemcitabine-lauric acid conjugate. Our data showed that SZY-200 could inhibit the proliferation of bladder cancer cells by inducing cell cycle arrest and apoptosis. The inhibitory effects were comparable to gemcitabine and CP-4126. Importantly, SZY-200 was independent of the membrane transport system in bladder cancer cells. Moreover, we found that lauric acid could also inhibit the proliferation of bladder cancer cells. SZY-200 could downregulate the expressions of PPARG and PTGS2 which were related to the occurrence and development of bladder cancer. Overall, these results indicate that SZY-200 could be an ideal candidate drug for further in vivo investigation.