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Chin J Integr Med. 2018 Jan;24(1):47-55. doi: 10.1007/s11655-017-2544-8. Epub 2017 Jul 25.

Ethanol extract of Ilex hainanensis Merr. exhibits anti-melanoma activity by induction of G1/S cell-cycle arrest and apoptosis.

Author information

1
College of Medicine, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China.
2
College of Clinical Chinese Medicine, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China.
3
Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China.
4
Chinese Medicine Hospital of Yangzhou City, Yangzhou, Jiangsu Province, 225009, China.
5
Oncology Business Unit, Wuxi AppTec. Inc, Shanghai, 200131, China.
6
College of Medicine, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China. jgz7718@sina.com.
7
College of Clinical Chinese Medicine, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China. jgz7718@sina.com.
8
Medical and Pharmaceutical Institute, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China. jgz7718@sina.com.

Abstract

OBJECTIVE:

To evaluate anti-melanoma effect of ethanol extract of Ilex hainanensis Merr. (IME) and elucidate its underlying mechanism.

METHODS:

Thirty-six tumor-bearing mice were randomized into 6 groups (n=6) as follows: model group, IME 25, 50, 100, and 200 mg/kg groups and dacarbazine (DTIC) 70 mg/kg group. The mice in the IME treatment groups were intragastrically administered with IME 25, 50, 100 or 200 mg/kg per day, respectively. The mice in the DTIC group were intraperitoneally injected with DTIC 70 mg/kg every 2 days. The drug administration was lasting for 14 days. The cell viability was evaluated by 3-(4,5-dime-thylthylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay. Flow cytometry was employed to detect cell cycle and apoptosis. The gene and protein expressions of nuclear factor κB-p65 (NF-κB-p65), Bcl-2, B-cell lymphomaextra large (Bcl-xL) and Bax were detected by quantitative real-time polymerase chain reaction and Western blot analyses. Caspases-3, -8, and -9 activities were detected using the colorimetric method. In addition, a B16-F10 melanoma xenograft mouse model was used to evaluate the anti-cancer activity of IME in vivo. Furthermore, a survival experiment of tumor-bearing mice was also performed to evaluate the possible toxicity of IME.

RESULTS:

IME significantly inhibited the proliferation of B16-F10 cells (P<0.01). Flow cytometric analysis showed that IME induced G1/S cell cycle arrest and apoptosis (both P<0.01). IME inhibited activation of NF-κB, decreased the gene and protein expressions of Bcl-2, Bcl-xL, and increased the gene and protein expressions of Bax (all P<0.01). In addition, IME induced the activation of Caspases-3, -8, and -9 in B16-F10 cells. The study in vivo showed that IME significantly reduced tumor volume (P<0.01), and the inhibitory rate came up to 68.62%. IME also induced large areas of necrosis and intra-tumoral apoptosis that correlated with a reduction in tumor volume. Survival experiment showed that treatment with IME for 14 days significantly prolonged survival time and 20% of mice in the IME 200 mg/kg group were still alive until the 50th day. Notably, IME showed no apparent side-effects during the treatment period.

CONCLUSION:

IME exhibited significant anti-melanoma activity in vitro and in vivo, suggesting that IME might be a promising effective candidate with lower toxic for malignant melanoma therapy.

KEYWORDS:

Chinese medicine; G1/S arrest; Ilex hainanensis Merr.; anti-melanoma activity; apoptosis; caspase; survival time

PMID:
28741062
DOI:
10.1007/s11655-017-2544-8
[Indexed for MEDLINE]

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