Prodelphinidins isolated from Chinese bayberry leaves induces apoptosis via the p53-dependent signaling pathways in OVCAR-3 human ovarian cancer cells

Fu,Yu; Ye,Xingqian; Lee,Malcolm; Rankin,Gary; Chen,Yi  Charlie

doi:10.3892/ol.2017.5813

Prodelphinidins isolated from Chinese bayberry leaves induces apoptosis via the p53-dependent signaling pathways in OVCAR-3 human ovarian cancer cells

Authors:
- Yu Fu
- Xingqian Ye
- Malcolm Lee
- Gary Rankin
- Yi Charlie Chen
View Affiliations

Affiliations: College of Biosystems Engineering and Food Science, Fuli Institute of Food Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China, College of Science, Technology and Mathematics, Alderson Broaddus University, Philippi, WV 26416, USA, Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
Published online on: March 6, 2017 https://doi.org/10.3892/ol.2017.5813
Pages: 3210-3218

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Chinese bayberry leaves are rich in prodelphinidins. Since the isolation and purification of prodelphinidins is difficult, the association between the degree of prodelphinidin polymerization and their anti‑carcinogenic activity remains ambiguous. The cytotoxic and apoptotic activities of prodelphinidin Chinese bayberry leaf extracts (PCBLs), oligomeric proanthocyanidins (OPAs) and polymeric proanthocyanidins (PPAs), isolated by normal‑phase preparative high‑performance liquid chromatography were investigated in OVCAR‑3 human ovarian cancer cells. The PCBLs, OPAs and PPAs inhibited cancer cell growth and induced apoptosis via the caspase‑dependent pathway. Apoptosis was triggered through the intrinsic pathway by upregulating the expression of several B‑cell lymphoma‑2 (Bcl‑2) family proapoptotic proteins, including p53‑upregulated modulator of apoptosis (PUMA), Bcl‑2‑associated X protein and Bcl‑2‑associated agonist of cell death, and by downregulating the antiapoptotic protein Bcl‑extra large. Apoptosis was also triggered through the extrinsic pathway via the upregulation of death receptor 5 (DR5) and Fas expression. In addition, OPAs and PPAs induced caspase‑dependent apoptosis at least partially through the inhibition of the protein kinase B signaling pathway. The knockdown of p53 by specific small interfering RNA resulted in the depletion of p53, and inhibited the OPA and PPA treatment‑induced increases in p53, which led to a decrease in the expression of p21, DR5, Fas, PUMA and phosphatase and tensin homolog proteins. These observations demonstrate that p53 is a mediator of OPA and PPA‑induced apoptosis in OVCAR‑3 cells. The PPAs exhibited stronger anti‑proliferative and pro‑apoptotic activities compared with OPAs and PCBLs. These results suggest that PCBLs, OPAs and PPAs may be useful for the treatment of ovarian cancer.

View Figures

View References

1	Nandakumar V, Singh T and Katiyar SK: Multi-targeted prevention and therapy of cancer by proanthocyanidins. Cancer Lett. 269:378–387. 2008. View Article : Google Scholar : PubMed/NCBI
2	Prior RL and Gu L: Occurrence and biological significance of proanthocyanidins in the American diet. Phytochemistry. 66:2264–2280. 2005. View Article : Google Scholar : PubMed/NCBI
3	de la Iglesia R, Milagro FI, Campión J, Boqué N and Martínez JA: Healthy properties of proanthocyanidins. Biofactors. 36:159–168. 2010. View Article : Google Scholar : PubMed/NCBI
4	Chen K, Xu C, Zhang B and Ferguson IB: Red bayberry: Botany and horticulture. Horticultural Rev. 30:83–114. 2004.
5	Zhang SM, Gao ZS, Xu CJ and Chen KS: Genetic diversity of Chinese bayberry (Myrica rubra Sieb. et Zucc.) accessions revealed by amplified fragment length polymorphism. Hort Sci. 44:487–491. 2009.
6	Fu Y, Qiao L, Cao Y, Zhou X, Liu Y and Ye X: Structural elucidation and antioxidant activities of proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves. PLoS One. 9:e961622014. View Article : Google Scholar : PubMed/NCBI
7	Yang H, Ye X, Liu D, Chen J, Zhang J, Shen Y and Yu D: Characterization of unusual proanthocyanidins in leaves of bayberry (Myrica rubra Sieb. et Zucc.). J Agric Food Chem. 59:1622–1629. 2011. View Article : Google Scholar : PubMed/NCBI
8	Miura T, Chiba M, Kasai K, Nozaka H, Nakamura T, Shoji T, Kanda T, Ohtake Y and Sato T: Apple procyanidins induce tumor cell apoptosis through mitochondrial pathway activation of caspase-3. Carcinogenesis. 29:585–593. 2008. View Article : Google Scholar : PubMed/NCBI
9	Han MH, Lee WS, Jung JH, Jeong JH, Park C, Kim HJ, Kim G, Jung JM, Kwon TK, Kim GY, et al: Polyphenols isolated from Allium cepa L. induces apoptosis by suppressing IAP-1 through inhibiting PI3K/Akt signaling pathways in human leukemic cells. Food Chem Toxicol. 62:382–389. 2013. View Article : Google Scholar : PubMed/NCBI
10	Dai GH, Meng GM, Tong YL, Chen X, Ren ZM, Wang K and Yang F: Growth-inhibiting and apoptosis-inducing activities of Myricanol from the bark of Myrica rubra in human lung adenocarcinoma A549 cells. Phytomedicine. 21:1490–1496. 2014. View Article : Google Scholar : PubMed/NCBI
11	Kaur M, Mandair R, Agarwal R and Agarwal C: Grape seed extract induces cell cycle arrest and apoptosis in human colon carcinoma cells. Nutr Cancer. 60:(Suppl 1). S2–S11. 2008. View Article : Google Scholar
12	Kroemer G and Martin SJ: Caspase-independent cell death. Nat Med. 11:725–730. 2005. View Article : Google Scholar : PubMed/NCBI
13	Huang C, Ma WY, Goranson A and Dong Z: Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis. 20:237–242. 1999. View Article : Google Scholar : PubMed/NCBI
14	Guan YQ, Li Z, Yang A, Huang Z, Zheng Z, Zhang L, Li L and Liu JM: Cell cycle arrest and apoptosis of OVCAR-3 and MCF-7 cells induced by co-immobilized TNF-α plus IFN-γ on polystyrene and the role of p53 activation. Biomaterials. 33:6162–6171. 2012. View Article : Google Scholar : PubMed/NCBI
15	Lin HY, Delmas D, Vang O, Hsieh TC, Lin S, Cheng GY, Chiang HL, Chen CE, Tang HY, Crawford DR, et al: Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol. J Cell Biochem. 114:1940–1954. 2013. View Article : Google Scholar : PubMed/NCBI
16	Li B, Gao Y, Rankin GO, Rojanasakul Y, Cutler SJ, Tu Y and Chen YC: Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells. Cancer Lett. 356:418–433. 2015. View Article : Google Scholar : PubMed/NCBI
17	Yang X, Fraser M, Moll UM, Basak A and Tsang BK: Akt-mediated cisplatin resistance in ovarian cancer: Modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res. 66:3126–3136. 2006. View Article : Google Scholar : PubMed/NCBI
18	Xia M, Knezevic D and Vassilev LT: p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation. Oncogene. 30:346–355. 2011. View Article : Google Scholar : PubMed/NCBI
19	Hsu CP, Lin YH, Chou CC, Zhou SP, Hsu YC, Liu CL, Ku FM and Chung YC: Mechanisms of grape seed procyanidin-induced apoptosis in colorectal carcinoma cells. Anticancer Res. 29:283–289. 2009.PubMed/NCBI
20	Singh T, Sharma SD and Katiyar SK: Grape proanthocyanidins induce apoptosis by loss of mitochondrial membrane potential of human non-small cell lung cancer cells in vitro and in vivo. PLoS One. 6:e274442011. View Article : Google Scholar : PubMed/NCBI
21	Dinicola S, Cucina A, Antonacci D and Bizzarri M: Anticancer effects of grape seed extract on human cancers: A review. J Carcinogenesis Mutagenesis. 8:60–70. 2014.
22	Dinicola S, Cucina A, Pasqualato A, D'Anselmi F, Proietti S, Lisi E, Pasqua G, Antonacci D and Bizzarri M: Antiproliferative and apoptotic effects triggered by Grape Seed Extract (GSE) versus epigallocatechin and procyanidins on colon cancer cell lines. Int J Mol Sci. 13:651–664. 2012. View Article : Google Scholar : PubMed/NCBI
23	Prasad R and Katiyar SK: Bioactive phytochemical proanthocyanidins inhibit growth of head and neck squamous cell carcinoma cells by targeting multiple signaling molecules. PLoS One. 7:e464042012. View Article : Google Scholar : PubMed/NCBI
24	Deprez S, Mila I, Huneau JF, Tome D and Scalbert A: Transport of proanthocyanidin dimer, trimer, and polymer across monolayers of human intestinal epithelial Caco-2 cells. Antioxid Redox Signal. 3:957–967. 2001. View Article : Google Scholar : PubMed/NCBI
25	Faria A, Mateus N, de Freitas V and Calhau C: Modulation of MPP+ uptake by procyanidins in Caco-2 cells: Involvement of oxidation/reduction reactions. FEBS Lett. 580:155–160. 2006. View Article : Google Scholar : PubMed/NCBI