Genomic analysis of pterostilbene predicts its antiproliferative effects against pancreatic cancer in vitro and in vivo

Abstract

Background: To investigate the inhibitory role of pterostilbene in pancreatic cancer, we conducted a genomic analysis of pterostilbene-treated pancreatic cancer cells. We also investigated the effect of pterostilbene upon the carcinogenic markers, manganese superoxide dismutase, cytochrome C, Smac/DIABLO, and STAT3 phosphorylation in vitro. The antiproliferative effects of pterostilbene were further evaluated in an in vivo model.

Methods: Pancreatic cancer cells were treated with pterostilbene and evaluated with DNA microarray analysis. Pterostilbene-treated cells were analyzed for cytochrome C, Smac/DIABLO, manganese superoxide dismutase (MnSOD)/antioxidant activity, and STAT3 phosphorylation using ELISA. Data were statistically analyzed using ANOVA. Pterostilbene was then administered to nude mice for 8 weeks, and tumor growth rates were recorded and statistically analyzed.

Results: Microarray analysis of pterostilbene-treated cells revealed upregulation of pro-apoptosis genes. In vitro, pterostilbene treatment altered levels of phosphorylated STAT3, MnSOD/antioxidant activity, cytochrome C, and Smac/DIABLO. In nude mice, oral pterostilbene inhibited tumor growth rates.

Conclusion: Pterostilbene alters gene expression in pancreatic cancer and increases the antiproliferative markers cytochrome C, Smac/DIABLO, and MnSOD/antioxidant activity. It was also shown to inhibit phosphorylated STAT3, a marker of accelerated tumorigenesis, and decrease pancreatic tumor growth in vivo. Further studies are warranted to elucidate the effects of pterostilbene in humans.

Fig. 1

MIA PaCa-2 cells treated with 25 and 50 μM pterostilbene had an increase in cytosolic cytochrome C when compared to control (***p< 0.001). However, 75 μM decreased cytosolic cytochrome C. PANC-1 cells treated with 25, 50, and 75 μM showed a dose-related increase in cytosolic cytochrome C release when compared to control (***p<0.001; **p<0.01; *p<0.05)

Fig. 2

MIA PaCa-2 cells treated with 75 μM pterostilbene had an increase in Smac/DIABLO when compared to control (***p<0.001). PANC-1 cells treated with 25 and 75 μM pterostilbene showed a dose-related increase in Smac/DIABLO when compared to control (***p<0.001; **p<0.01)

Fig. 3

MIA PaCa-2 and PANC-1 cells treated with 25 and 50 μM pterostilbene had a significant increase in MnSOD enzymatic activity when compared to controls (**p<0.01)

Fig. 4

In MIA PaCa-2 cells, pterostilbene decreased MDA adducts (*p<0.05; **p<0.01). In PANC-1, MDA protein adducts were decreased with 75 μM pterostilbene (**p<0.01)

Fig. 5

Inhibition of phosphorylated STAT3 was seen in both MIA PaCa-2 (*p< 0.05; **p<0.01; ***p<0.001) and PANC-1 cells (*** p<0.001) with pterostilbene treatment

Fig. 6

a Control ×100, viable tumor in upper left, necrosis in lower right. b Treatment group ×100, viable tumor in upper left, necrosis in lower right. The volume of necrosis was approximately the same for all treatment doses and the control. c Control ×400, cell morphology and cytology. d Treatment group ×400, cell morphology and cytology were similar for all treatment doses and the control