Zeriouh Wafa, Nani Abdelhafid, Belarbi Meriem, Dumont Adélie, de Rosny Charlotte, Aboura Ikram, Ghanemi Fatima Zahra, Murtaza Babar, Patoli Danish, Thomas Charles, Apetoh Lionel, Rébé Cédric, Delmas Dominique, Khan Naim Akhtar, Ghiringhelli François, Rialland Mickael, Hichami Aziz
Laboratory of Natural Products, Aboubekr Belkaid University, Tlemcen, Algeria.
Department of Natural and Life Sciences, African University Ahmed Draia, Adrar, Algeria.
PLoS One. 2017 Feb 17;12(2):e0170823. doi: 10.1371/journal.pone.0170823. eCollection 2017.
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.
源自天然产物的膳食多酚因其对癌症的化学预防特性而备受关注。在本研究中，我们调查了油橄榄叶酚提取物（PEOL）对小鼠模型肿瘤生长及结肠癌细胞系细胞死亡的影响。我们评估了油橄榄叶浸剂对无胸腺裸鼠体内HCT116（人结肠癌细胞系）异种移植瘤生长的作用。我们观察到富含油橄榄叶多酚的浸剂在体内限制了HCT116肿瘤的生长。对PEOL在两种人结直肠癌细胞系上的研究表明，PEOL可诱导HCT116和HCT8细胞凋亡。我们证明了PEOL可激活半胱天冬酶-3、-7和-9，并且用泛半胱天冬酶抑制剂N-苄氧羰基-Val-Ala-Asp-氟甲基酮（z-VAD-fmk）预处理可预防PEOL诱导的细胞死亡。我们观察到线粒体途径参与了PEOL诱导的凋亡，这表现为活性氧（ROS）生成、线粒体膜电位降低以及细胞色素c释放。PEOL诱导的细胞内Ca2+浓度升高代表了参与线粒体功能障碍、ROS诱导的内质网（ER）应激以及PEOL诱导的凋亡的早期事件，因为线粒体钙摄取抑制剂钌红可抑制PEOL的凋亡作用，BAPTA/AM可抑制PEOL诱导的ROS生成，最后，N-乙酰-L-半胱氨酸可逆转PEOL的ER应激和凋亡作用。这些结果表明，油橄榄叶中的多酚可能具有作为结直肠癌化学预防剂的强大潜力。
