Abstract
Statins are cholesterol reduction agents that exhibit anti-cancer activity in several human cancers. Because autophagy is a crucial survival mechanism for cancer cells under stress conditions, cooperative inhibition of autophagy acts synergistically with other anti-cancer drugs. Thus, this study investigates whether combined treatment of atorvastatin and autophagy inhibitors results in enhancing the cytotoxic effects of atorvastatin, upon human bladder cancer cells, T24 and J82, in vitro. To measure cell viability, we performed the EZ-Cytox cell viability assay. We examined apoptosis by flow cytometry using annexin-V/propidium iodide (PI and western blot using procaspase-3 and poly (ADP-ribose) polymerase (PARP) antibodies. To examine autophagy activation, we evaluated the co-localization of LC3 and LysoTracker by immunocytochemistry, as well as the expression of LC3 and p62/sequestosome-1 (SQSTM1) by western blot. In addition, we assessed the survival and proliferation of T24 and J82 cells by a clonogenic assay. We found that atorvastatin reduced the cell viability of T24 and J82 cells via apoptotic cell death and induced autophagy activation, shown by the co-localization of LC3 and LysoTracker. Moreover, pharmacologic inhibition of autophagy significantly enhanced atorvastatin-induced apoptosis in T24 and J82 cells. In sum, inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death in human bladder cancer cells in vitro, providing a potential therapeutic approach to treat bladder cancer.
Highlights
Urinary bladder cancer is the ninth most common cancer in the world, posing a crucial public health problem because of its high aggressiveness and poor prognosis [1]
In the cells treated for 24 h, only the 50 μM concentration of atorvastatin reduced cell viability remarkably compared to a control, whereas 30, 40 and 50 μM concentrations reduced cell viability significantly after 48 and 72 h of treatment (Figure 1A)
These results show that atorvastatin can reduce the cell viability of bladder cancer cells in a dose- and time-dependent manner
Summary
Urinary bladder cancer is the ninth most common cancer in the world, posing a crucial public health problem because of its high aggressiveness and poor prognosis [1]. To 80% are non-muscle invasive tumors that can be managed by combined therapy with transurethral resection and intravesical chemotherapy [2]. More than 50% of superficial bladder cancers will recur, and eventually 10% to 20% of recurrent tumors give rise to muscle invasive tumors [3]. Given the high recurrence rates even after surgical resection, multimodal therapy consisting of surgical approaches combined with radiotherapy and chemotherapy is typically considered for the patients with muscle-invasive bladder cancer [5]. Such a therapeutic strategy still has unfavorable clinical outcomes, and there is growing interest in alternative therapeutic approaches to manage bladder cancer
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