Abstract
Quercetin is a naturally existing compound and shows attractive anticancer properties for a variety of solid tumors including glioma, bladder cancer, hepatocellular carcinoma, breast cancer, hematological malignancies and prostate carcinoma. However, these anticancer properties have not been clinically approved due to unclear mechanistic information and its low bioactivity. In our previous study, we elucidated that quercetin activates AMPK pathway which is the major mechanism for its unique anticancer effect in bladder cancer. In the present study, we are trying to enhance its bioactivity by chemical modification using fluorination approach to prepare novel chemical entities, based on the principle of intermediate derivative method (IDM). The compound we obtained is named 8-trifluoromethyl-3,5,7,3′,4′-O-pentamethyl- quercetin (TFQ), characterized by NMR spectra and mass spectrum (MS). The results from MTT and cologenic assay in two human and one murine bladder cancer cell lines showed that TFQ exhibits more potent inhibition on the three bladder cancer cell lines than quercetin (Que) although this enhanced effects is not very dramatic. Furthermore, we found that the survival of normal bladder cells PEBC was not significantly suppressed by TFQ compared with Que. Western blot analysis showed that TFQ possess more potent AMPK activation than Que. The downstream of AMPK was further examined by western blot. TFQ treatment is able to inactivate mTOR signaling pathway with the regulation of mTOR, 4EBP1 and P70S6K. These results demonstrated that the fluorinated quercetin derivative TFQ inhibits bladder cancer cell growth through the AMPK/mTOR pathway. Altogether, our findings suggest that TFQ could serve as a new potential therapeutic agent for bladder cancer more effective than Que.
Highlights
Bladder cancer is the fifth most common malignancy in United States, with an estimated 76,960 new cases and 16,390 deaths in 2016 [1,2]
TFQ treatment is able to inactivate mammalian target of rapamycin (mTOR) signaling pathway with the regulation of mTOR, 4EBP1 and P70S6K. These results demonstrated that the fluorinated quercetin derivative TFQ inhibits bladder cancer cell growth through the AMPK/mTOR pathway
In our quest to develop novel quercetin derivatives with increased potency for AMPK activation and mTOR inhibition, we found that compared with quercetin, TFQ activated AMPK with significantly greater potencies
Summary
Bladder cancer is the fifth most common malignancy in United States, with an estimated 76,960 new cases and 16,390 deaths in 2016 [1,2]. Even though transurethral resection has served as the standard treatment, recurrence and metastasis are often seen in clinic [3]. The commonest way to prevent recurrence and progression is supplemented with intravesical chemotherapy or immunosuppressive agents [4, 5]. Despite these brave efforts, outcomes have changed very little for the past three decades [6]. Metabolism of bladder cancer represents a key issue for www.impactjournals.com/oncotarget cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis [7]
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