Olive Mill Wastewater Inhibits Growth and Proliferation of Cisplatin- and Gemcitabine-Resistant Bladder Cancer Cells In Vitro by Down-Regulating the Akt/mTOR-Signaling Pathway.

Jochen Rutz,Sebastian Maxeiner,Igor Tsaur,Felix K.-H Chun,Roman A Blaheta,Eva Juengel

doi:10.3390/nu14020369

Abstract

Bladder cancer patients whose tumors develop resistance to cisplatin-based chemotherapy often turn to natural, plant-derived products. Beneficial effects have been particularly ascribed to polyphenols, although their therapeutic relevance when resistance has developed is not clear. The present study evaluated the anti-tumor potential of polyphenol-rich olive mill wastewater (OMWW) on chemo-sensitive and cisplatin- and gemcitabine-resistant T24, RT112, and TCCSUP bladder cancer cells in vitro. The cells were treated with different dilutions of OMWW, and tumor growth and clone formation were evaluated. Possible mechanisms of action were investigated by evaluating cell cycle phases and cell cycle-regulating proteins. OMWW profoundly inhibited the growth and proliferation of chemo-sensitive as well as gemcitabine- and cisplatin-resistant bladder cancer cells. Depending on the cell line and on gemcitabine- or cisplatin-resistance, OMWW induced cell cycle arrest at different phases. These differing phase arrests were accompanied by differing alterations in the CDK-cyclin axis. Considerable suppression of the Akt-mTOR pathway by OMWW was observed in all three cell lines. Since OMWW blocks the cell cycle through the manipulation of the cyclin-CDK axis and the deactivation of Akt-mTOR signaling, OMWW could become relevant in supporting bladder cancer therapy.

Highlights

Bladder cancer is the most common tumor of the urinary system worldwide [1], with approximately 550,000 diagnosed cases and more than 200,000 deaths every year [2]
The same efficacy was seen with DU145 and PC3 prostate cancer cells, whereby the growth of the prostate cancer cell line LNCaP was already blocked by an OMWWdilution of 1:5000 [19]
We provide evidence that olive mill wastewater (OMWW) profoundly acts on the growth and proliferation of bladder cancer cells, both in chemo-sensitive as well as gemcitabine- and cisplatin-resistant cells

Summary

Introduction

Bladder cancer is the most common tumor of the urinary system worldwide [1], with approximately 550,000 diagnosed cases and more than 200,000 deaths every year [2]. Transitional cell carcinoma) represents the predominant histologic type in the United States and Western Europe, accounting for approximately 90% of all bladder cancers [3]. EAU Guidelines recommend firstline treatment with the MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) or GC (gemcitabine, cisplatin) scheme [3]. These therapeutic approaches remain palliative, and overall survival is similar, with a median survival of 14.0 months for GC and 15.2 months for MVAC [6]. More than 200 appurtenant clinical trials are in progress, testifying to the urgency to improve current treatment protocols to prevent or delay drug non-responsiveness [9]

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Conclusion