Arctigenin in combination with quercetin synergistically enhances the antiproliferative effect in prostate cancer cells

Abstract

Scope We investigated whether a combination of two promising chemopreventive agents arctigenin and quercetin increases the anti-carcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Methods and results Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of arctigenin and quercetin alone or in combination for 48h. The anti-proliferative activity of arctigenin was 10-20 fold stronger than quercetin in both cell lines. Their combination synergistically enhanced the anti-proliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arctigenin demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. Conclusion The combination of arctigenin and quercetin, that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer.

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

“…The general profiles of Arc-responsive genes differ between AR mutated LNCaP cells and AR wild-type LAPC-4 cells (Table 1). This was also observed in our previous studies 16 . In xenograft tumors, Arc significantly reduced both the total and nuclear AR expression.…”

“…The anti-carcinogenic activity of Arc has been demonstrated in vitro and in a few animal studies in several cancers, including pancreatic, breast, and lung cancer, associated with the induction of apoptosis, inhibition of proliferation and modulations of multiple signaling pathways 12-14 . We previously demonstrated in vitro in prostate cancer that the combination with Arc at lower doses significantly enhanced the anti-proliferative effect of several other phytochemicals like curcumin, green tea polyphenols, and quercetin 15,16 . The present study provides in vivo evidence of the potent anti-tumor strength of Arc in mouse models and provides insight into the underlying molecular mechanisms.…”

The effect of quercetin on microRNA expression: A critical review

“…Moreover, the LAPC-4 cell line treated by arctigenin showed almost the same expression of miR-19b and miR-21 even displayed a decreasing trend compared to arctigenin/quercetin samples. However, quercetin monotherapy was usually weaker and, surprisingly, quercetin displayed an opposite behavior for miR-21 in both cell lines 65 . MiR-19b and miR-21 are usually designated as oncogenic 66 and their downregulation is recognized as a positive effect.…”

“…Wang and colleagues 65 used on a quercetin combination as well, in this case a mix of quercetin and arctigenin evaluated in prostate cancer cell models (LAPC-4 and LNCaP cell lines). They compared miRNA expression of control cells with those treated with the arctigenin/quercetin combination and uncovered several miRNAs that were downregulated.…”

Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways

“…The PI3K/AKT pathway that is crucial in cell survival is activated in various cancers including prostate cancer (Wang et al, 2015). Accumulating reports indicate possible crosstalk between PI3K/Akt/mTOR and androgen receptor signalling that directly regulates androgen receptor expression and activation (Morgan et al, 2009).…”