Abstract
MiR-106b is an oncomir and a potential target for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects on lung cancer through modulations of miR-106b and its downstream target. We found that GSE significantly down-regulated miR-106b in a variety of lung neoplastic cells and increased cyclin-dependent kinase inhibitor 1A (CDKN1A) mRNA and protein (p21) levels. Transfection of miR-106b mimics reversed the up-regulations of CDKN1A mRNA and p21, abrogated the GSE induced anti-proliferative and anti-invasive properties in lung cancer cells. Oral gavage of leucoselect phytosome (LP), a standardized GSE to athymic nude mice down-regulated MIR106B mRNA and miR-106b expressions, and increased CDKN1A mRNA expression in tumor xenografts, correlating to significant reduction of tumor growth. To assess bioavailability, GSE and metabolites in plasma levels, between 60–90 minutes after gavage of LP were measured by LC/MS at treatment week 4 and 8. A novel bioactivity assay was also developed using lung homogenates from treated mice co-cultured with human lung cancer cells. LP-treated mouse lung homogenates significantly reduced proliferations of various lung cancer cells. Our findings reveal novel antineoplastic mechanisms by GSE, further define the pharmacokinetics and pharmacodynamics of LP, and support the continued investigation of LP against lung cancer.
Highlights
Derived from seeds of grapes (Vitis vinifera), grape seed procyanidin extract (GSE) is high in procyanidins with strong antioxidant capabilities [1, 2]
We report for the first time, the roles of miR-106b, and its downstream target cyclin-dependent kinase inhibitor 1A (CDKN1A) or p21, in mediating the anti-neoplastic properties of GSE against non-small cell lung cancer (NSCLC) and Small cell lung cancer (SCLC)
We show that GSE down-regulates www.oncotarget.com miR-106b, which in turn up-regulates CDKN1A gene mRNA expression and its respective protein p21 production in our lung cancer models
Summary
Derived from seeds of grapes (Vitis vinifera), GSE is high in procyanidins with strong antioxidant capabilities [1, 2]. We recently reported that modulations of oncogenic microRNA (miRNA) or oncomir miR-19a/b, contributed to the antineoplastic properties of GSE against non-small cell lung cancer (NSCLC) and bronchial premalignant cells [8]. Ample studies have shown that specific miRNA signatures in biospecimens had remarkable sensitivity and specificity in discriminating cancer patients from healthy subjects [12, 13]. These characteristics support the potential of oncomirs as therapeutic targets and surrogate endpoint biomarkers (SEBM) for lung cancer treatment and chemoprevention studies
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