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Background: Doxorubicin (Dox) is widely used to treat progressed bladder cancer after transurethral resection. The use of Dox-chemotherapy has been limited due to induced drug resistance and cumulative cardiotoxic effects. N-benzyladriamycin-14-valerate (AD198), a novel derivative of Dox, has a potential to become a more effective treatment than Dox by overcoming drug resistance and cardio-toxicity as shown in the rodent model of lymphoma in vivo. The purpose of this study was to compare the efficacy of Dox and AD198 and explore their mechanisms in inhibition on human bladder cancer cells in vitro.Methods: We evaluated the effects of Dox and AD198 on cell viability of human transitional cell carcinoma (TCC) cell lines T24 and UMUC3 by MTS assay in vitro. The effects of Dox and AD198 on cell apoptosis were determined by caspase 3/7 assay, generation of reactive oxygen species (ROS), and Western Blotting (WB) analysis.Results: AD198 was more effective than Dox in inhibition of cell viability of T24 and UMUC3 cells in vitro. Both Dox and AD198 significantly increased the generation of ROS and induced apoptosis in caspase-dependent and -independent manner in T24 and UMUC3 cells. AD 198 induced significantly higher production of ROS as compared to Dox in human TCC cells. Dox and AD198 activated the pro-apoptotic p38 MAPK pathway; however, on the other hand also increased phosphorylation of AKT, an anti-apoptotic signaling pathway, in T24 and UMUC3 cells. Combined treatment of PI3K inhibitor (LY294002) with Dox or AD198 inhibited cell viability of T24 and UMUC3 cells more effectively than any of drug treatments alone.Conclusions: These data suggest that AD198 as novel derivative of Dox, could be a used as effective treatment for bladder cancer. Dox and AD198 induced PI3K/AKT signaling pathway that is a one of the indicators of pro-survival and possible drug-resistance mechanisms of chemotherapies in bladder cancer. Combined therapies of Dox or AD198 with inhibitors of PI3K/AKT signaling pathway might lead to more effective treatment outcome for patients diagnosed with bladder cancer based on our in vitro experiments. [ABSTRACT FROM AUTHOR]

Anthracycline-based chemotherapy, such as doxorubicin (Dox), while effective against many solid tumors, is not widely used for head and neck cancers. In this study, we evaluated the efficacy of Dox, and its derivative AD198 in human, canine, and feline oral squamous cell carcinomas cells (OSCC) in vitro. Dox and AD198 had significant an anti-proliferative effect on human, canine, and feline OSCC cells in dose-dependent manner. AD198 inhibited cell proliferation more effectively than Dox in tested OSCC cells. In the human oral squamous cell carcinoma SCC25 cells, Dox and AD198 increased the production of reactive oxygen species and subsequently increased apoptosis through activation of caspase signaling pathway. Dox and AD198 increased activation of AKT, ERK1/2, and p38 MAPK signaling pathways in tested OSCC cells by dose-dependent manner. The efficacy of Dox and AD198 treatments in inhibition of cell proliferation was increased in tested OSCC when combined with PI3K/AKT inhibitor, LY294002 treatment. Inhibition of PI3K/AKT reduced Dox- and AD198-induced activation of ERK1/2 and further increased Dox- and AD198-induced phosphorylation of p38 MAPK in OSCC. Our results suggest that the anthracycline therapies, such as Dox or AD198, can be more effective for treatment of OSCC when combined with inhibitors of the PI3K/AKT pathway. J. Cell. Biochem. 118: 2615-2624, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)