13-[CH 2 CO-Cys-(Bzl)-OBzl]-Berberine: Exploring The Correlation Of Anti-Tumor Efficacy With ROS And Apoptosis Protein

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Abstract

Background

The discovery of novel derivative of berberine (BBR) having higher anti-tumor activity in vivo is of clinical importance. In this profile, 13-[CH ₂CO-Cys-(Bzl)-OBzl]-berberine (13-Cys-BBR) was prepared for related assays.

Purpose

The object of preparation and evaluation is to show the advantages of 13-Cys-BBR over BBR in both in vitro and in vivo anti-tumor actions, furthermore to correlate the proliferation of cancer cells with ROS formation and anti-apoptosis protein (XIAP) expression inside cancer cells.

Methods

Transwell chamber was used to simulate the intestinal and cell wall for bioavailability evaluation; MTT assay was used to evaluate the in vitro anti-proliferation activity; fluorescein isothiocyanate content was used to represent ROS level in HCT-8 cells; Western blot assay was used to quantify the expression of XIAP, caspase-3, and poly ADP-ribose polymerase in HCT-8 cells; and S180 mouse model was used to evaluate the in vivo anti-tumor activity.

Results

In vitro the IC ₅₀ values (~15–40 μM) of 13-Cys-BBR against the proliferation of eight cancer cell lines were significantly lower than those of BBR (~25–140 μM); the content of ROS formed inside HCT-8 cells treated by 13-Cys-BBR was ~3.44-folds higher than that inside HCT-8 cells treated by BBR; the expression of XIAP in HCT-8 cells treated by 13-Cys-BBR was ~1.21-folds lower than that in HCT-8 cells treated by BBR; the tumor weight of S180 mice orally treated by 2 μmol/kg/day of 13-Cys-BBR (~1.5 g) was significantly lower than that of S180 mice orally treated by 2 μmol/kg/day of BBR (~2.5 g); and the active pocket of XIAP was more suitable for 13-Cys-BBR than for BBR.

Conclusion

The anti-tumor action correlates with ROS and apoptosis protein, which suggests 13-Cys-BBR is a promising candidate for preclinical study.

Related collections

Most cited references 26

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Berberine ameliorates chronic relapsing dextran sulfate sodium-induced colitis in C57BL/6 mice by suppressing Th17 responses

Yan-hong Li, Hai-tao Xiao, Dong-dong Hu … (2016)

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Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma.

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Hepatocellular carcinoma (HCC) is an invasive cancer with a high rate of recurrence and metastasis. Agents with anti-proliferative as well as anti-metastatic activity will be ideal for effective treatment. Here, we demonstrated that berberine, an isoquinoline alkaloid, harbored potent anti-metastatic and anti-proliferative activities in vivo. Using an orthotopic model of HCC (MHCC-97L), which spontaneously develops lung metastases (one of the most common sites of HCC metastasis), we found that berberine treatment (10mg/kg/2days) significantly reduced lung metastasis from the liver tumors by ~85% (quantitated by bioluminescence emitted from lung metastases). Histological examination also confirmed the reduced incidence and number of lung metastases in berberine-treated mice. Furthermore, berberine effectively suppressed extra-tumor invasion of the primary HCC implant into the surrounding normal liver tissue, illustrating its potent anti-metastatic action in vivo. Consistent with previous reports in other cancer, berberine's anti-tumor activity was accompanied by suppression of cellular proliferation, invasiveness and HIF-1α/VEGF signaling. Strikingly, further mechanistic investigation revealed that berberine exerted profound inhibitory effect on the expression of Id-1, which is a key regulator for HCC development and metastasis. Berberine could suppress the transcription level of Id-1 through inhibiting its promotor activity. Specific downregulation of Id-1 by knocking down its RNA transcripts in HCC cells inhibited cellular growth, invasion and VEGF secretion, demonstrating the functional relevance of Id-1 downregulation induced by berberine. Lastly, berberine's anti-proliferative and anti-invasive activities could be partially rescued by Id-1 overexpression in HCC models, revealing a novel anti-cancer/anti-invasive mechanism of berberine via Id-1 suppression.

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Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives.

Ning Wang, Hor-Yue Tan, Lei Li … (2015)

The antineoplastic property of Coptidis Rhizoma and berberine was correlated with its traditional use of clearing internal fire, removing damp-heat and counteracting toxic pathogens.

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Author and article information

Journal

Journal ID (nlm-ta): Onco Targets Ther

Journal ID (iso-abbrev): Onco Targets Ther

Journal ID (publisher-id): OTT

Journal ID (pmc): ott

Title: OncoTargets and therapy

Publisher: Dove

ISSN (Electronic): 1178-6930

Publication date (Electronic): 05 December 2019

Publication date Collection: 2019

Volume: 12

Pages: 10651-10662

Affiliations

[1 ]Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, People’s Republic of China

[2 ]Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, School of Pharmaceutical Sciences, Capital Medical University , Beijing 100069, People’s Republic of China

[3 ]Beijing Laboratory of Biomedical Materials and Key Laboratory of Biomedical Materials of Natural Macromolecules, Beijing University Of Chemical Technology , Beijing 100026, People’s Republic of China

Author notes

Correspondence: Shiqi Peng; Ming Zhao Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Capital Medical University , No. 10, Youanmenwaixitoutiao, Fengtai District, Beijing100069, People’s Republic of ChinaTel +86 1083911528; +86 1083911535Fax +86 1083911528; +86 1083911533 Email sqpeng@bjmu.edu.cn; mingzhao@bjmu.edu.cn

Article

Publisher ID: 231035

DOI: 10.2147/OTT.S231035

PMC ID: 6901133

SO-VID: f085bcc4-3715-4eab-aba8-21a6d4955432

License:

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