Phytosterols and phytostanols and the hallmarks of cancer in model organisms: A systematic review and meta-analysis

Critical Reviews in Food Science and Nutrition

Nov 2020

DOI: 10.1080/10408398.2020.1835820

Citations:35

Influential Citations:2

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

In vivo preclinical cancer models; animals included mice and rats (all studies except one used zebrafish). Study designs encompassed xenograft assays, mutagen-induced tumors, and spontaneous genetic cancer models. Some studies used DMBA- or NMU-induced carcinogenesis. Overall, 32 records were screened for inclusion; 22 were suitable for meta-analysis; data were extracted in duplicate.

Intervention

Phytosterol/phytostanol regimens given to cancer-model animals as dietary supplements or injections. Doses varied from the equivalent of 3 mg per person per week to 75 g per person per day (human-equivalent dosing). Routes included chow-integrated oral administration (PO), oral gavage (OG), and intravenous injection (IV). Common compounds studied included sitosterol (SITO) as the major component, with campesterol (CAMP), stigmasterol (STIG), fucosterol (FUCO), and daucosterols (DAUC/DAUL) also used, sometimes as mixtures (e.g., ~60% sitosterol, 30% campesterol, 5% stigmasterol). Durations ranged from weeks to months, with long-term exposures reported up to about 44 weeks for SITOSTEROL-containing regimens.

Results

Phytosterols and phytostanols reduced primary and metastatic tumor burden across cancer sites. In breast and colorectal cancer, pAKT and metastasis markers (MMP2/MMP9), angiogenesis markers (VEGF, CD31), and proliferation markers (Ki67, PCNA) were consistently reduced; tumor growth was inhibited in many models. Very high doses, especially CAMP-rich mixtures, sometimes caused adverse effects (gut health issues and intestinal adenoma formation). PSS have potential as cost-effective anti-cancer agents with a plausible mechanism of action, and may be explored as preventive or adjunctive therapy, potentially synergizing with PARP inhibitors, gemcitabine, or vemurafenib; human clinical data are needed.

Limitations

High heterogeneity across animal studies (I2 often >75%), varying cancer models, compounds, routes, and doses; reliance on preclinical data limits translation to humans; some regimens used extremely high doses with adverse effects; incomplete reporting of ethical approvals and potential biases; evidence may be affected by publication bias.

Abstract

Abstract Phytosterols and phytostanols are natural products present in vegetable oils, nuts, and seeds, or added to consumer food products whose intake is inversely associated with incidence and prognosis of several cancers. Randomized cancer prevention trials in humans are unfeasible due to time and cost yet the cellular processes and signaling cascades that underpin anti-cancer effects of these phytochemicals have been explored extensively in vitro and in preclinical in vivo models. Here we have performed an original systematic review, meta-analysis, and qualitative interpretation of literature published up to June 2020. MEDLINE, Scopus, and hand-searching identified 408 unique records that were screened leading to 32 original articles that had investigated the effects of phytosterols or phytostanols on cancer biology in preclinical models. Data was extracted from 22 publications for meta-analysis. Phytosterols were most commonly studied and found to reduce primary and metastatic tumor burden in all cancer sites evaluated. Expression of pAKT, and markers of metastasis (alkaline phosphatase, matrix metalloproteases, epithelial to mesenchymal transcription factors, lung and brain colonization), angiogenesis (vascular endothelial growth factor, CD31), and proliferation (Ki67, proliferating cell nuclear antigen) were consistently reduced by phytosterol treatment in breast and colorectal cancer. Very high dose treatment (equivalent to 0.2–1 g/kg body weight not easily achievable through diet or supplementation in humans) was associated with adverse events including poor gut health and intestinal adenoma development. Phytosterols and phytostanols are already clinically recommended for cardiovascular disease risk reduction, and represent promising anti-cancer agents that could be delivered in clinic and to the general population at low cost, with a well understood safety profile, and now with a robust understanding of mechanism-of-action. Graphical Abstract show less