PMID- 29655853 OWN - NLM STAT- MEDLINE DCOM- 20181011 LR - 20181011 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 221 DP - 2018 Jul 15 TI - Total saponins of Albiziae Cortex show anti-hepatoma carcinoma effects by inducing S phase arrest and mitochondrial apoptosis pathway activation. PG - 20-29 LID - S0378-8741(18)30449-5 [pii] LID - 10.1016/j.jep.2018.04.015 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Albiziae Cortex (AC) is a widely used traditional medicine in China. It is possess various properties to treat insomnia, traumatic injuries, diuresis, sthenia, and confusion. Total saponins of Albiziae Cortex (TSAC) are the most abundant bioactive components of AC, which were reported to show significant anti-tumor effects in vivo and in vitro. But the underlying mechanism of TSAC remained to be revealed. AIM OF STUDY: In this study, we investigated the anti-hepatoma carcinoma effects and the potential mechanism of TSAC in vivo and in vitro. MATERIALS AND METHODS: We first purified TSAC from crude extracts and characterized the major bioactive compounds by high performance liquid chromatography (HPLC). Effects of TSAC on viability of various hepatoma carcinoma cell lines were measured by MTT. Inhibition on cell proliferation was analysed using colony formation assay. Cell cycle distribution was revealed by flow cytometry. The apoptotic cells were observed by Hoechst 33258 staining and acridine orange (AO)/ethidium bromide (EB) double staining. Microstructures of apoptotic cells were examined by Transmission electron microscopy (TEM). The mitochondrial membrane potential were determined by JC-1 staining. Western blot was used to investigate the effects of TSAC on apoptosis-related proteins, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax), and S-phase related protein cyclin A, cyclin E and cyclin-dependent kinases 2 (CDK2). Effects on tumor growth was assessed by H22-bearing ICR mice. RESULTS: TSAC significantly decreased the hepatoma carcinoma cell viability and inhibited HepG2 cell colony formation in a concentration-dependent manner. We also found that TSAC inhibited HepG2 cell growth via induction of S phase arrest. Further study showed that TSAC significantly down-regulated the expressions of cyclin A, cyclin E and CDK2 in HepG2 cells. Meanwhile, TSAC could effectively induce mitochondria-dependent caspase apoptosis pathway activation. Furthermore, TSAC increased the expression of pro-apoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2. In vivo assay showed that the anti-tumor effects of TSAC were significantly augmented without increasing toxicity in H22-bearing ICR mice. CONCLUSION: TSAC could inhibit cell proliferation through inducing S phase arrest and activate cell apoptosis via mitochondria-dependent apoptosis pathway. Therefore, TSAC could be a promising agent in clinical trials for anti-hepatoma carcinoma treatment. CI - Copyright (c) 2018. Published by Elsevier B.V. FAU - Qian, Yi AU - Qian Y AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. FAU - Han, Qing-Hua AU - Han QH AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. FAU - Wang, Li-Chao AU - Wang LC AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, China. FAU - Guo, Qiang AU - Guo Q AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. FAU - Wang, Xu-Da AU - Wang XD AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. FAU - Tu, Peng-Fei AU - Tu PF AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. FAU - Zeng, Ke-Wu AU - Zeng KW AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: ZKW@bjmu.edu.cn. FAU - Liang, Hong AU - Liang H AD - State Key Laboratory of Natural and Biomimetic Drugs, Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: lianghong@bjmu.edu.cn. LA - eng PT - Journal Article DEP - 20180412 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (Cyclin A) RN - 0 (Cyclin E) RN - 0 (Plant Extracts) RN - 0 (Proto-Oncogene Proteins c-bcl-2) RN - 0 (Saponins) RN - EC 2.7.11.22 (Cdk2 protein, mouse) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 2) SB - IM MH - *Albizzia MH - Animals MH - Antineoplastic Agents, Phytogenic/pharmacology/*therapeutic use MH - Apoptosis/drug effects MH - Cell Cycle Checkpoints/drug effects MH - Cell Line, Tumor MH - Cyclin A/metabolism MH - Cyclin E/metabolism MH - Cyclin-Dependent Kinase 2/metabolism MH - Humans MH - Liver Neoplasms, Experimental/*drug therapy/metabolism/pathology MH - Male MH - Membrane Potential, Mitochondrial/drug effects MH - Mice, Inbred ICR MH - Mitochondria/drug effects/physiology MH - Phytotherapy MH - Plant Extracts/chemistry MH - Proto-Oncogene Proteins c-bcl-2/metabolism MH - S Phase/drug effects MH - Saponins/pharmacology/*therapeutic use MH - Tumor Burden OTO - NOTNLM OT - Anti-hepatoma carcinoma OT - Apoptosis OT - Cell cycle arrest OT - Mitochondrial pathway OT - Total saponins of Albiziae Cortex EDAT- 2018/04/16 06:00 MHDA- 2018/10/12 06:00 CRDT- 2018/04/16 06:00 PHST- 2018/02/06 00:00 [received] PHST- 2018/04/01 00:00 [revised] PHST- 2018/04/11 00:00 [accepted] PHST- 2018/04/16 06:00 [pubmed] PHST- 2018/10/12 06:00 [medline] PHST- 2018/04/16 06:00 [entrez] AID - S0378-8741(18)30449-5 [pii] AID - 10.1016/j.jep.2018.04.015 [doi] PST - ppublish SO - J Ethnopharmacol. 2018 Jul 15;221:20-29. doi: 10.1016/j.jep.2018.04.015. Epub 2018 Apr 12.