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Abstract
Activation of the NFκB pathway is often associated with advanced cancer and has thus been regarded as a rational therapeutic target. Wedelia chinensis is rich in luteolin, apigenin, and wedelolactone that act synergistically to suppress androgen receptor activity in prostate cancer. Interestingly, our evaluation of a standardized Wedelia chinensis herbal extract (WCE) concluded its efficacy on hormone-refractory prostate cancer through systemic mechanisms. Oral administration of WCE significantly attenuated tumor growth and metastasis in orthotopic PC-3 and DU145 xenografts. Genome-wide transcriptome analysis of these tumors revealed that WCE suppressed the expression of IKKα/β phosphorylation and downstream cytokines/chemokines, e.g., IL6, CXCL1, and CXCL8. Through restraining the cytokines expression, WCE reduced tumor-elicited infiltration of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and endothelial cells into the tumors, therefore inhibiting angiogenesis, tumor growth, and metastasis. In MDSCs, WCE also reduced STAT3 activation, downregulated S100A8 expression and prevented their expansion. Use of WCE in combination with docetaxel significantly suppressed docetaxel-induced NFκB activation, boosted the therapeutic effect and reduced the systemic toxicity caused by docetaxel monotherapy. These data suggest that a standardized preparation of Wedelia chinensis extract improved prostate cancer therapy through immunomodulation and has potential application as an adjuvant agent for castration-resistant prostate cancer.
Highlights
Current hormonal and chemotherapeutic approaches improve survival in patients with prostate cancer (PCa), relapse typically occurs after 1–2 years and often results in lethality[1]
Wedelia chinensis extract (WCE) dose-dependently suppressed the growth of both androgen receptor (AR)-expressing PCa cells (LNCaP and 22Rv1) and hormone-refractory PCa cells (PC-3 and DU145) (Fig. 1a)
Our unpublished data showed that 12 hours following a single oral dose of 100 mg/kg WCE by gavage in mice, wedelolactone, luteolin, and apigenin were still present at low but detectable levels in prostate and liver, not kidney spleen, and others, indicating three active compounds selectively distributed in prostate and the herbal compounds do not accumulate in most tissues to cause potential side effect
Summary
Current hormonal and chemotherapeutic approaches improve survival in patients with prostate cancer (PCa), relapse typically occurs after 1–2 years and often results in lethality[1]. To extend survival in men with CRPC, numerous phase III clinical trials have investigated the use of novel agents either as adjuvant or neoadjuvant with docetaxel. Application of nutraceuticals, such as curcumin, to supplement conventional therapy was found to be well tolerated and accepted by patients in clinical trials[12]. Clinical studies showed that docetaxel-treated patients exhibit increased CXCL8 expression, and upregulation of CXCL8 promotes the survival of PCa cells rendering docetaxel treatment less effective[14,15]. WCE as an anti-inflammatory therapy inhibited the growth of CRPC and exhibited a beneficial effect when used in combination with docetaxel chemotherapy by intensifying the anti-tumor effect and reducing docetaxel-induced cytokine expression and toxicity
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