γ-Tocotrienol and α-Tocopherol Ether Acetate Enhance Docetaxel Activity in Drug-Resistant Prostate Cancer Cells

Abstract

Prostate cancer is the second most commonly diagnosed cancer in men, and metastatic prostate cancer is currently incurable. Prostate cancer frequently becomes resistant to standard of care treatments, and the administration of chemotherapeutic drugs is often accompanied by toxic side effects. Combination therapy is one tool that can be used to combat therapeutic resistance and drug toxicity. Vitamin E (VE) compounds and analogs have been proposed as potential non-toxic chemotherapeutics. Here we modeled combination therapy using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize mixture compositions, to determine whether combinations of three chemotherapeutic agents: γ-tocotrienol (γ-T3), α-tocopherol ether acetate (α-TEA), and docetaxel (DOC), would prove more effective than docetaxel alone in the treatment of human prostate cancer cells. Response surfaces were generated for cell viability, and the optimal treatment combination for reducing cell viability was calculated. We found that a combination of 20 µM γ-T3, 30 µM α-TEA, and 25 nm DOC was most effective in the treatment of PC-3 cells. We also found that the combination of γ-T3 and α-TEA with DOC decreased the amount of DOC required to reduce cell viability in PC-3 cells and ameliorated therapeutic resistance in DOC-resistant PC-3 cells.

Revisiting the therapeutic potential of tocotrienol

“…132 The best combination treatment was identified as gamma-tocotrienol with alpha-tocopherol ether acetate and docetaxel that could evade drug resistance in prostate cancer treatment than docetaxel given alone. 132 The synergistic action of gamma-tocotrienol and polysaccharopeptide (PSP) has been investigated in which, prostate cancer cell growth, proliferation, and cytotoxicity were seen to reduce, through the mediation of AMPK. 133 The researchers of this study had observed an increase in AMPK with the simultaneous inactivation of acetyl-co A carboxylase, an integral step in cellular energy homeostasis, evidenced by the Ser 79-activated phosphorylation.…”

Utilizing mixture design response surface methodology to determine effective combinations of plant derived compounds as prostate cancer treatments

“…Since berberine and wogonin were found in combination so often in the optimal treatments and reduced cells up to greater than 50%, we further tested a MDRSM combination on a docetaxel‐ resistant PC3 cell line. Previously in our lab, we grew the DR‐PC3 cell line to demonstrate chemotherapy resistant cells 6 . We treated the DR‐PC3 cell line with a three‐way combination of shikonin, berberine, and wogonin.…”

“…This problem is more likely to occur with the compounds that have a stepwise shape to their IC50 curve (Figure 1). Perhaps choosing a higher drug concentration for the 100% treatments, that is points 1–3 in Figure 2A, would ensure the concentrations used at the subsequent mixture points, points 4–10 in Figure 2A, are biologically relevant for subsequent studies, as used by Asay et al Furthermore, the MDRSM model can be improved by adding additional points to augment the simplex model and improve the fit and allow for a more exact predicted optimal treatment 6 …”

“…For each cell line, we added 10% fetal bovine serum (Corning, 35‐010‐CV) and 1% antibiotic (Hyclone, SV30010) and kept them in a 37°C humidified 5% CO2 incubator from passages 4–30. Docetaxel‐Resistant Clones were previously prepared in the lab as reported by Asay 2020 6 …”

“…Specifically, research is being done to improve PC treatment through a combination of chemotherapy with bioactive compounds. For example, treatment of PC3 cells with docetaxel and vitamin E led to a significant decrease in the cell viability compared to docetaxel treatment alone 6 . Researchers are also studying bioactive compounds found in traditional Chinese medicines (TCM) to determine their chemotherapeutic effects 7 .…”