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Updated: Aug 7, 2025
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Necroptosis Induced by Delta-Tocotrienol Overcomes Docetaxel Chemoresistance in Prostate Cancer Cells
Marina Montagnani Marelli1, Giangiacomo Beretta2, Roberta Manuela Moretti1
1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.
Abstract:
Prostate cancer (PCa) represents the fifth cause of cancer death in men. Currently, chemotherapeutic agents for the treatment of cancers, including PCa, mainly inhibit tumor growth by apoptosis induction. However, defects in apoptotic cellular responses frequently lead to drug resistance, which is the main cause of chemotherapy failure. For this reason, trigger non-apoptotic cell death might represent an alternative approach to prevent drug resistance in cancer. Several agents, including natural compounds, have been shown to induce necroptosis in human cancer cells. In this study we evaluated the involvement of necroptosis in anticancer activity of delta-tocotrienol (δ-TT) in PCa cells (DU145 and PC3). Combination therapy is one tool used to overcome therapeutic resistance and drug toxicity. Evaluating the combined effect of δ-TT and docetaxel (DTX), we found that δ-TT potentiates DTX cytotoxicity in DU145 cells. Moreover, δ-TT induces cell death in DU145 cells that have developed DTX resistance (DU-DXR) activating necroptosis. Taken together, obtained data indicate the ability of δ-TT to induce necroptosis in both DU145, PC3 and DU-DXR cell lines. Furthermore, the ability of δ-TT to induce necroptotic cell death may represent a promising therapeutical approach to overcome DTX chemoresistance in PCa.
Insights
Delta-tocotrienol (δ-TT) triggers necroptosis, a non-apoptotic cell death pathway, in prostate cancer cells. This finding offers a promising strategy to overcome chemotherapy resistance in prostate cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men.
- Current chemotherapies often fail due to drug resistance, frequently linked to defects in apoptosis.
- Targeting non-apoptotic cell death pathways like necroptosis presents an alternative strategy to combat chemoresistance.
Purpose of the Study:
- To investigate the role of necroptosis in the anticancer activity of delta-tocotrienol (δ-TT) against prostate cancer cells.
- To evaluate the efficacy of δ-TT, alone and in combination with docetaxel (DTX), in overcoming chemoresistance.
Main Methods:
- Utilized DU145 and PC3 prostate cancer cell lines, including docetaxel-resistant (DU-DXR) variants.
- Assessed the induction of necroptosis by δ-TT.
- Evaluated the combined effects of δ-TT and DTX on cell viability and cytotoxicity.
Main Results:
- Delta-tocotrienol (δ-TT) was found to induce necroptosis in DU145, PC3, and DU-DXR prostate cancer cells.
- δ-TT potentiated the cytotoxic effects of docetaxel (DTX) in DU145 cells.
- δ-TT effectively induced cell death via necroptosis in DTX-resistant prostate cancer cells.
Conclusions:
- Delta-tocotrienol (δ-TT) activates necroptosis in various prostate cancer cell lines, including chemoresistant ones.
- δ-TT shows potential as a therapeutic agent to overcome docetaxel resistance in prostate cancer.
- Targeting necroptosis with δ-TT represents a promising approach for refractory prostate cancer treatment.
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