Nitidine chloride inhibits hepatic cancer growth via modulation of multiple signaling pathways.

Abstract

BACKGROUND:

The development of hepatic cancer is tightly regulated by multiple intracellular signaling pathways. Therefore, most currently-used anti-tumor agents, which typically target single intracellular pathway, might not always be therapeutically effective. Additionally, long-term use of these agents probably generates drug resistance and unacceptable adverse effects. These problems increase the necessity for the development of new chemotherapeutic approaches. Nitidine chloride (NC), a natural benzophenanthridine alkaloid, has been shown to inhibit cancer growth via induction of cell apoptosis and suppression of cancer angiogenesis. But the precise mechanisms of its tumorcidal activity are not well understood.

METHODS:

To further elucidate the precise mechanisms of its anti-tumor activity, using a hepatic cancer mouse xenograft model, the human hepatic cancer cell lines (HepG2, HCCLM3, Huh7), and umbilical vein endothelial cells (HUVEC), here we evaluate the effect of NC on tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms.

RESULTS:

We found that NC treatment resulted in significant decrease in tumor volume and tumor weight respectively, but didn't affect body weight changes. Additionally, NC treatment dose- and time-dependently reduced the cell viability of all three hepatic cell lines. Moreover, NC suppressed the activation of STAT3, ERK and SHH pathways; and altered the expression of critical target genes including Bcl-2, Bax, Cyclin D1, CDK4, VEGF-A and VEGFR2. These molecular effects resulted in the promotion of apoptosis, inhibition of cell proliferation and tumor angiogenesis.

CONCLUSIONS:

Our findings suggest that NC possesses a broad range of anti-cancer activities due to its ability to affect multiple intracellular targets, suggesting that NC could be a novel multi-potent therapeutic agent for the treatment of hepatic cancer and other cancers.

• Authors: Jiumao Lin, Aling Shen, Hongwei Chen, Jun Liao, Teng Xu, Liya Liu, Jing Lin, Jun Peng
• Journal: BMC cancer (BMC Cancer) Vol. 14 Pg. 729 (Sep 30 2014) ISSN: 1471-2407 [Electronic] England
• PMID: 25266147 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• BAX protein, human
• BCL2 protein, human
• Benzophenanthridines
• Proto-Oncogene Proteins c-bcl-2
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• bcl-2-Associated X Protein
• nitidine
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Apoptosis
• Benzophenanthridines (pharmacology)
• Cell Survival (drug effects)
• Gene Expression (drug effects)
• Hep G2 Cells
• Human Umbilical Vein Endothelial Cells (drug effects, physiology)
• Humans
• Liver Neoplasms (blood supply, drug therapy, pathology)
• MAP Kinase Signaling System
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice, Inbred BALB C
• Mice, Nude
• Neovascularization, Pathologic (drug therapy)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction
• Tumor Burden
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)