Abstract 2316: In vitro and in vivo anticancer potential of adapalene, a third-generation retinoid against bladder cancer

Abstract

Abstract Bladder cancer is the ninth most common cause of cancer, with the highest recurrence rate of any malignancy. By 2025, the seven major markets for bladder cancer are expected to reach $1.17B. The disease is highly prevalent in developed nations. While smoking and industrialization have been closely linked to the development of the disease, the chances of new cases are expected to rise in the coming years. The current chemotherapy strategy involves myriad standard of care (SOC) drugs, including the promising regimen of Programmed Cell Death-1 (PD-1) modulators. However, they exhibit several limitations like adverse effects and drug resistance followed by relapse. Hence, there remains an unmet medical need in bladder cancer treatment including patients who do not respond following PD-1 therapy. In this scenario, alternate drug therapy, with a novel mechanism of action would be the path forward. This study attempts to establish the role of adapalene in the treatment of bladder cancer and to elucidate the underlying mechanism of action. Adapalene is a FDA approved, third generation synthetic retinoid drug, mainly used as a topical application in the treatment of acne vulgaris. It has been reported to inhibit cyclin-dependent kinase 2, which is an important regulator in progressing the cell cycle from G1 to S phase. This brings about a cell cycle arrest, consequently leading to apoptosis of the tumor cells. Few reports implicate its efficacy in colorectal and hepatoma carcinoma cell lines. However, its anti-cancer efficacy against bladder cancer as a stand-alone and/or in combination with the SOC drug has not yet been reported. Adapalene anti-proliferative potential was tested against a panel of five bladder cancer cell lines, including patient derived cells (PDX). The results indicated a dose dependent cytotoxicity with a mean IC50 of 6.84 µM and 14.01 µM in a 2D and 3D setup respectively. Further, we studied the effect of adapalene alone or in combination with cisplatin in colony formation assay using bladder cancer cell lines. Interestingly, it showed a synergistic effect in combination with cisplatin in 1218L (PDX) and T24; while the effect was additive in case of 1036L (PDX). Similarly, adapalene by itself and in combination showed significant apoptosis in HTB5 and HTB9 cells. Likewise, differential gene and protein expression studies using drug alone and combination showed promising results. Additionally, in vivo efficacy study was performed in 1218L model using adapalene alone and in combination with cisplatin. Adapalene by itself showed a significant antitumor efficacy. Notably, the combination group shows tumor growth inhibition by 78% as compared to cisplatin and adapalene alone, where the growth inhibition was 64% and 59% respectively. Thus, the promising anti-tumor efficacy of adapalene clearly demonstrates that it could be a potential candidate alone and in combination against bladder cancer. Citation Format: Jeevan Ghosalkar, Srikanth Iyer, Geena Malhotra, Kalpana Joshi. In vitro and in vivo anticancer potential of adapalene, a third-generation retinoid against bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2316.