Abstract
Among the many stilbenoids found in a variety of berries, resveratrol and pterostilbene are of particular interest given their potential for use in cancer therapeutics and prevention. We purified four stilbenoids from R. undulatum and found that pterostilbene inhibits cancer cell proliferation more efficiently than rhapontigenin, piceatannol and resveratrol. To investigate the underlying mechanism of this superior action of pterostilbene on cancer cells, we utilized a reverse-phase protein array followed by bioinformatic analysis and found that the ATM/CHK pathway is modified by pterostilbene in a lung cancer cell line. Given that ATM/CHK signaling requires p53 for its biological effects, we hypothesized that p53 is required for the anticancer effect of pterostilbene. To test this hypothesis, we used two molecularly defined precancerous human bronchial epithelial cell lines, HBECR and HBECR/p53i, with normal p53 and suppressed p53 expression, respectively, to represent premalignant states of squamous lung carcinogenesis. Pterostilbene inhibited the cell cycle more efficiently in HBECR cells compared to HBECR/p53i cells, suggesting that the presence of p53 is required for the action of pterostilbene. Pterostilbene also activated ATM and CHK1/2, which are upstream of p53, in both cell lines, though pterostilbene-induced senescence was dependent on the presence of p53. Finally, pterostilbene more effectively inhibited p53-dependent cell proliferation compared to the other three stilbenoids. These results strongly support the potential chemopreventive effect of pterostilbene on p53-positive cells during early carcinogenesis.
Highlights
Despite advances in our understanding of the molecular mechanisms of carcinogenesis, cancer remains one of the leading causes of death worldwide.[1]
We investigated the therapeutic and preventive effect of PT on non-small cell lung cancer cell (NSCLC, A549) and precancerous human bronchial epithelial cell (HBEC) lines using stilbenoids purified from the roots of R. undulatum, which has long been used in traditional medicine in Asia
We further examined the mechanism underlying p53 phosphorylation upon PT treatment and observed that the phenomenon in A549 lung cancer cells was observable in precancerous cell lines
Summary
Despite advances in our understanding of the molecular mechanisms of carcinogenesis, cancer remains one of the leading causes of death worldwide.[1]. One of such is chemoprevention, which involves preventing carcinogenesis or delaying of cancer progression through taking of dietary or pharmaceutical agents.[2,3,4,5,6] Carcinogenesis is a multistep process that involves
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