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

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.

From antiquity to contemporary times: how olive oil by-products and waste water can contribute to health

“…Bladder cancer is a threatening tumor of the urinary system, approximately 90% of all bladder cancers worldwide are urothelial carcinoma. OMWW injection solution (Burg-Apotheke) was tested on resistant parental bladder cancer cell lines (T24, TCCSUP, and RT112) for 48 and 72 h proliferation ( 83 ). The clonogenic cell growth, number and size were significantly diminished in a concentration dependent manner.…”

“…The OMWW treatment reduced pAkt (24 and 72 h), pRaptor (24 h), Rictor (24 and 72 h), pRictor, and pmTOR Akt–mTOR axis. It is assumed that OMWW’s ability to inhibit growth and proliferation, both in chemosensitive and gemcitabine- and cisplatin-resistant bladder cancer cells, is associated with cell cycling arrest through cyclin-CDK axis manipulation and suppression of Akt/mTOR pathway activation ( 83 ).…”

Plant-Derived Sulforaphane Suppresses Growth and Proliferation of Drug-Sensitive and Drug-Resistant Bladder Cancer Cell Lines In Vitro

“…Cell lines were defined to be resistant when they no longer responded to cisplatin or gemcitabine, or when the response to the drugs was strongly restricted, compared to the response of the sensitive cells. All further experiments were then conducted by comparing drug-sensitive to drug-resistant cells that were permanently exposed to 1 µg/mL (TCCSUP, RT112, T24) or 2 µg/mL cisplatin (RT4) or 10 ng/mL (TCCSUP) or 20 ng/mL gemcitabine (RT4, RT112, T24) [22].…”

Medicago sativa Extracts Enhance the Anticancer Efficacy of GEM in PANC-1 Cells through Apoptosis Induction and BAX/BCL-2/CASP3 Expression Modulation

“…Despite the emergence of novel chemotherapy approaches in recent decades, medication resistance remains a signi cant barrier [4]. To enhance the PC patients' overall survival rates, a large body of research has investigated the combination of gemcitabine (GEM) with different agents, e.g., natural products (NPs) [5][6][7][8]. NPs are vital in developing innovative treatments, accounting for over 60% of all recognized pharmaceuticals [9].…”