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Mitochondrial mechanisms in benzo[a]pyrene-induced carcinogenesis and chemoprevention by polyphenols



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Naturally occurring polyphenols in fruits and vegetables have been shown to exhibit anticancer characteristics. Although some roles of polyphenols in cancer prevention have been previously described, an involvement of mitochondrial mechanisms has not been well-studied. Also, while mitochondrial dysfunction has been identified in several cancer cells and is correlated with poor prognosis, less is known about the involvement of mitochondrial changes in carcinogenesis and neoplastic transformation. In an in vitro model of cancer initiation and promotion using Bhas 42 fibroblasts, we investigated the involvement of mitochondrial changes induced by benzo[a]pyrene (B[a]P) and possible roles of different polyphenols in preventing carcinogenesis and neoplastic transformation, through inhibiting oxidative stress, inducing mitochondrial biogenesis, and ameliorating mitochondrial dysfunction. Bhas 42 mouse fibroblast cells were pre-treated with 5 μM polyphenols (resveratrol, quercetin, catechin, cyanidin, cyanidin-3-glucoside (C3G), and berberine) for 2h for most experiments followed by treatment with 4 μM B[a]P for 12h, 24h and 72h. Different experiments including measuring intracellular reactive oxygen species (ROS), mitochondrial superoxide, gene expression, mitochondrial content, and neoplastic transformation were conducted. B[a]P induced oxidative stress by increasing intracellular ROS and mitochondrial superoxide generation, as well as induced UCP2 expression compared to untreated cells. Most of the polyphenols prevented these effects; however, only anthocyanins (cyanidin and C3G) and berberine decreased B[a]P-induced mitochondrial superoxide generation. B[a]P induced neoplastic transformation almost 5-fold while resveratrol and quercetin inhibited this effect and resveratrol had the strongest effect, inhibiting by 75%. B[a]P also decreased mitochondrial content, as well as decreased SIRT1 activity, ERRα expression, and expression of some mitochondrial respiratory subunits (NDUFS8, ATP5A1, and CYB). All polyphenols increased at least one of these factors with different effectiveness. B[a]P exposure also produced mitochondrial dysfunction, decreased mitochondrial membrane potential (MMP) and ATP content by 25% and 28%, respectively, while some polyphenols such as resveratrol and quercetin completely prevented B[a]P-induced mitochondrial dysfunction. The increased mitochondrial biogenesis by resveratrol corresponded with decreased ROS generation and can be suggested as a plausible mechanism by which resveratrol inhibited B[a]P-induced neoplastic transformation more strongly than other studied polyphenols. The study showed that B[a]P impaired mitochondrial biogenesis and induced mitochondrial dysfunction, oxidative stress, and neoplastic transformation, whereas different polyphenols protected against these effects, with resveratrol showing the most robust effects. The results shed new light into mitochondrial mechanisms by which polyphenols may prevent cancer initiation and progression.



Polyphenols, cancer prevention



Doctor of Philosophy (Ph.D.)






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