Inhibition of the PI3K/AKT signaling pathway increases efficacy of doxorubicin and its derivative AD198 in bladder and oral cancers

Doxorubicin (Dox) is a successful chemotherapy to treat various cancers, including bladder and oral cancers. Many patients initially respond to Dox-based regimens, however often cancers become resistant. A novel derivatives of Dox, e.g. N-benzyladriamycin-14-valerate (AD198), have been developed to overcome Dox-induced drug resistance and cardiotoxicity. The purpose of this thesis was to determine the efficacy of AD198 and Dox in bladder and oral cancers in vitro.

Part-I of this dissertation focuses on the bladder cancer, including discussing risk factors, diagnosis, staging, and current treatment options, following by a description of altered molecular mechanisms responsible cancer progression. This section also focuses on alternative experimental drugs and current clinical trials designed to target specific molecular markers of bladder cancer.

Part-II of this dissertation compares the efficacy of AD198 and Dox and its molecular mechanisms of action in human T24 and UMUC3 bladder cells in vitro. AD198 was more effective than Dox in inhibition of cell viability of T24 and UMUC3 cells. Both Dox and AD198 significantly induced apoptosis in caspase-dependent and -independent manners. Dox and AD198 activated the pro-apoptotic p38 MAPK pathway; however, they also increased phosphorylation of AKT, a pro-survival 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 drug treatment alone.

Part-III of this dissertation discusses oral cancer, with special focus on causes, diagnosis, treatment, molecular pathogenesis, and potential molecular targets for treatments.

Part IV of this dissertation focuses on evaluation of the efficacy of Dox and its novel derivative AD198 in human (SCC25 and 1483), canine K9OSCC-Abby, and feline (FeOSCC-Sidney) oral squamous cell carcinoma cells in vitro. Dox and AD198 had a better anti-proliferative effect than Dox in human and canine OSCC. Our results suggest that the combined therapy of an anthracycline compound with inhibitor of PI3K/AKT pathway is a more effective treatment.

Part V of this dissertation discusses the implications of these studies and examines current literature on the potential of targeting PI3K/AKT to increase the efficacy of anthracycline treatments in bladder and oral cancers.