Abstract
Dietary polyphenols, derived from natural products, have received a great interest for their chemopreventive properties against cancer. In this study, we investigated the effects of phenolic extract of the oleaster leaves (PEOL) on tumor growth in mouse model and on cell death in colon cancer cell lines. We assessed the effect of oleaster leaf infusion on HCT116 (human colon cancer cell line) xenograft growth in athymic nude mice. We observed that oleaster leaf polyphenol-rich infusion limited HCT116 tumor growth in vivo. Investigations of PEOL on two human CRC cell lines showed that PEOL induced apoptosis in HCT116 and HCT8 cells. We demonstrated an activation of caspase-3, -7 and -9 by PEOL and that pre-treatment with the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), prevented PEOL-induced cell death. We observed an involvement of the mitochondrial pathway in PEOL-induced apoptosis evidenced by reactive oxygen species (ROS) production, a decrease of mitochondrial membrane potential, and cytochrome c release. Increase in intracellular Ca2+ concentration induced by PEOL represents the early event involved in mitochondrial dysfunction, ROS-induced endoplasmic reticulum (ER) stress and apoptosis induced by PEOL, as ruthenium red, an inhibitor of mitochondrial calcium uptake inhibited apoptotic effect of PEOL, BAPTA/AM inhibited PEOL-induced ROS generation and finally, N-acetyl-L-cysteine reversed ER stress and apoptotic effect of PEOL. These results demonstrate that polyphenols from oleaster leaves might have a strong potential as chemopreventive agent in colorectal cancer.
Highlights
The colorectal cancer (CRC) is the third most prevalent cancer in the world and is the fourth leading cause of death
We investigated the effect of polyphenol-rich infusion from oleaster leaves on xenograft HCT116 tumor growth in nude mice and determined the molecular mechanism of the pro-apoptotic effect of phenolic extract from oleaster leaves (PEOL) in HCT116 and HCT8 colon cancer cell lines
We found that oleaster leaf infusion diminished significantly tumor growth by two fold that reached only 200 mm2 after 31 days of HCT116 injection (Fig 1)
Summary
The colorectal cancer (CRC) is the third most prevalent cancer in the world and is the fourth leading cause of death. Increasing number of reported cases of colon cancer in recent years has made this form of cancer a major health concern [2]. The major cases of colorectal cancers are considered sporadic, not caused by an inherited mutation; only 5–15% are caused by hereditary factors. It has been reported in different epidemiological studies that besides age and inflammation, the individual lifestyle like dietary habits, smoking, alcohol consumption and physical activity are significant risk factors for the development of CRC [3]. There has been increasing interest to find natural products able to contribute to the fight against CRC and improve current treatment [6]
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