The Combination of Omega-3 Stearidonic Acid and Docetaxel Enhances Cell Death over Docetaxel Alone in Human Prostate Cancer Cells

Abstract

Background: Docetaxel (DOC), or Taxotere, is an anthracycline antibiotic used to treat multiple types of cancer. It is a first-line chemotherapy treatment for patients with metastasized, hormone-resistant prostate cancer (PCa) or for patients with high-risk, localized PCa that could benefit from early chemotherapy treatment. Previously, we showed that stearidonic acid (SDA), an omega-3 fatty acid, enhances the cytotoxicity of doxorubicin (DOX) in human PCa cells. This observation suggests that PCa therapies using SDA and chemotherapeutic drugs in combination offer attractive possibilities for developing treatments that ameliorate toxic side effects of some commonly used chemotherapy drugs.Objectives: We used androgen-resistant PC3 and DU 145 cells derived from human prostate cancer to quantify the effects of combined SDA and DOC on proliferation/viability and on the production of pro-apoptotic caspases 9 and 3. We also compared the effects of SDA with those of BAY, a pharmacological inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), in androgen-sensitive LNCaP cells. Finally, we qualitatively and quantitatively assessed the drug combination on androgen receptor (AR) and peroxisome proliferator-activated receptor gamma (PPARγ) expression in LNCaP and PC3 cells, respectively.Methods: The half maximal inhibitory concentration (IC50) and combination indices of SDA and DOC in PC3 and DU 145 cells were determined using the MTT cell viability assay. To quantify the effects of SDA and BAY on NF-ĸB activity, we used luciferase reporter assays in LNCaP cells that were stably transduced with lentiviral vectors carrying NF-ĸB response element sequence upstream of the luciferase gene sequence. AR and PPARγ expression were assessed by western blotting and immunocytochemistry. We considered caspase 9 and 3 cleavage to be apoptosis markers and determined the drug combination effect on the extent of that cleavage by western blot analysis.Results: The cytotoxic effects of DOC were synergistically enhanced by SDA when the two were added to DU145 and PC3 cell cultures. Combination index (CI) analyses based on the Chou-Talalay method and mass action law showed synergistic interaction with CI <1. SDA suppressed TNFα-induced NF-κB activity similarly to BAY. The SDA/DOC combination down regulated testosterone (T)-induced AR and troglitazone-induced PPARγ protein expression when compared to using the drugs singly. Similarly, the SDA/DOC combination induced caspase 9 and 3 production and cleavage suggesting apoptosis induction. Like our DOX studies, this work provides proof-of-concept for using SDA and DOC in combination to reduce the dose, and therefore the toxicity, of DOC and possibly increasing the survival benefit in DOC clinical translation studies.

Encapsulation and Controlled Release of Resveratrol Within Functionalized Mesoporous Silica Nanoparticles for Prostate Cancer Therapy

“…The underlying mechanism involves the role of hypoxia inducible factor (HIF) which regulates the expression of proteins that contribute to the oncogenesis and enable the cancer cells to survive under hypoxic conditions (Vaupel, 2004). Docetaxel (Doc) has been considered as a standard first line therapy in prostate cancers (Francini and Sweeney, 2016; Mansour et al, 2018; Singh et al, 2018). However, the survival rate remains only modest owing to rapid resistance to Doc acquired by patients (Qian et al, 2018).…”

The nicotinamide phosphoribosyltransferase antagonist FK866 inhibits growth of prostate tumour spheroids and increases doxorubicin retention without changes in drug transporter and cancer stem cell protein expression

“…Cytostatic anthracyclines are generally used in clinical therapy to treat multiple types of cancer. It is a first‐line chemotherapy treatment for patients with metastasized, hormone‐resistant prostate cancer (PCa) or for patients with high‐risk, localized PCa that could benefit from early chemotherapy treatment 19 . Generally, chemotherapy is associated with severe side effects, which increase with the dose of the applied chemotherapeutic.…”

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling

“…A model incorporating stearidonic acid, TxB3, l -Homocitrulline, and PI (20:3/18:0) showed the best predictive ability with an AUROC of 0.8186. Stearidonic acid could enhance the cytotoxic effects of chemotherapy agents such as docetaxel in human prostate cancer cells and canine lymphoid tumor cells [ 26 , 27 ]. Thromboxane B3 is the stable hydrolysis product of Thromboxane A3 synthesized from eicosapentaenoic acid by COX and thromboxane synthase.…”