Grape seed proanthocyanidins (GSPs) inhibit the growth of cervical cancer by inducing apoptosis mediated by the mitochondrial pathway

Qing Chen; Xiao-Fang Liu; Peng-Sheng Zheng

doi:10.1371/journal.pone.0107045

Grape seed proanthocyanidins (GSPs) inhibit the growth of cervical cancer by inducing apoptosis mediated by the mitochondrial pathway

PLoS One. 2014 Sep 4;9(9):e107045. doi: 10.1371/journal.pone.0107045. eCollection 2014.

Authors

Qing Chen¹, Xiao-Fang Liu², Peng-Sheng Zheng³

Affiliations

¹ The Department of Reproductive Medicine, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China; The Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, China.
² The Department of Reproductive Medicine, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China; The Department of Pharmacology, Medical College of Xi'an Jiaotong University, Xi'an, China.
³ The Department of Reproductive Medicine, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China; The Department of Biochemistry and Molecular Biology, Medical College of Xi'an Jiaotong University, Xi'an, China; The Section of Cancer Research, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of the People's Republic of China, Xi'an, China.

Abstract

Grape seed proanthocyanidins (GSPs), a biologically active component of grape seeds, have been reported to possess a wide array of pharmacological and biochemical properties. Recently, the inhibitory effects of GSPs on various cancers have been reported, but their effects on cervical cancer remain unclear. Here, we explored the effect of GSPs on cervical cancer using in vitro and in vivo models. In vitro, the treatment of HeLa and SiHa cells with GSPs resulted in a significant inhibition of cell viability. Further investigation indicated that GSPs led to the dose-dependent induction of apoptosis in cancer cells. The underlying mechanism was associated with increased expression of the pro-apoptotic protein Bak-1, decreased expression of the anti-apoptotic protein Bcl-2, the loss of mitochondrial membrane potential, and the activation of caspase-3, suggesting that GSPs induced cervical cancer cell apoptosis through the mitochondrial pathway. In addition, the administration of GSPs (0.1%, 0.2%, and 0.4%, w/v) as a supplement in drinking water significantly inhibited the tumor growth of HeLa and SiHa cells in athymic nude mice, and the number of apoptotic cells in those tumors was also increased significantly. Taken together, our studies demonstrated that GSPs could inhibit the growth of cervical cancer by inducing apoptosis through the mitochondrial pathway, which provides evidence indicating that GSPs may be a potential chemopreventive and/or chemotherapeutic agent for cervical cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / pharmacology*
Apoptosis / drug effects*
Apoptosis / genetics
Caspase 3 / genetics
Caspase 3 / metabolism
Cell Line, Tumor
Female
Gene Expression Regulation, Neoplastic*
Grape Seed Extract / pharmacology*
Humans
Membrane Potential, Mitochondrial / drug effects
Mice
Mice, Nude
Mitochondria / drug effects*
Mitochondria / metabolism
Mitochondria / pathology
Proanthocyanidins / pharmacology*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Signal Transduction / drug effects
Transplantation, Heterotopic
Tumor Burden / drug effects
Uterine Cervical Neoplasms / drug therapy*
Uterine Cervical Neoplasms / genetics
Uterine Cervical Neoplasms / metabolism
Uterine Cervical Neoplasms / pathology
Xenograft Model Antitumor Assays
bcl-2 Homologous Antagonist-Killer Protein / agonists
bcl-2 Homologous Antagonist-Killer Protein / genetics
bcl-2 Homologous Antagonist-Killer Protein / metabolism

Substances

Antineoplastic Agents, Phytogenic
Bak1 protein, mouse
Grape Seed Extract
Grape Seed Proanthocyanidins
Proanthocyanidins
Proto-Oncogene Proteins c-bcl-2
bcl-2 Homologous Antagonist-Killer Protein
Bcl2 protein, mouse
Casp3 protein, mouse
Caspase 3

Grants and funding

The work was supported by a grant from the National Natural Science Fund for Distinguished Young Scientists (No. 30725043), a general grant (No. 81270715) and a youth grant (No. 31201118) from the National Natural Science Foundation of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.