Plant-based omega-3 stearidonic acid enhances antitumor activity of doxorubicin in human prostate cancer cell lines

Doxorubicin (DOX) is a first choice cytostatic drug in treatment of many cancers but among its side effects is cardiac toxicity. Stearidonic omega-3 fatty acid (SDA) has cardiac protective qualities and, therefore, we investigated the combinatory effects of DOX and SDA on proliferation/viability in the human prostate cancer (PCa) cell lines LNCaP, PC3, and DU145 as well as possible modulatory effects on expression of androgen receptor (AR), peroxisome proliferator-activated receptor gamma (PPAR, and nuclear factor kappa-lightchain-enhancer of activated B cells (NF-B) nuclear transcription factors implicated in tumorigenesis. The median inhibitory effects (IC50) of SDA were 601, 116, 145 M and that of DOX were 802, 761, 363 nM in LNCaP, PC3 and DU145, respectively. Equipotent combinations of DOX and SDA based on 2-fold dilutions and constant combination ratios derived from the above IC50 values suggested anticancer synergism with a combination index (CI) of less than 1 as determined using the Chou-Talalay method based on the medianeffect equation and the mass action law. Stearidonic acid strongly inhibited TNF-activated NF-B in stably transduced LNCaP cells. We used immunocytochemistry, real-time PCR, western blotting, and transactivation assays to demonstrate inhibition of agonist-activated AR and PPAR expression following treatment with DOX and SDA singly or in combination. This study provides proof-of-concept for using DOX and SDA in combination to reduce dose and toxicity of DOX in PCa clinical translation studies.