BND-12, a novel nonhaematotoxic naphthalimide derivative, inhibits tumour growth and metastasis of hepatocellular carcinoma.

Abstract

OBJECTIVES:

Naphthalimides have shown potent antitumour activity against a variety of murine and human cancer cells. However, most of them have been abandoned because of a poor therapeutic index and haematotoxicity, such as amonafide. To overcome these disadvantages, many novel naphthalimide derivatives have been designed and synthesized as antitumour agents.

METHODS:

The cytotoxicity of 6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl)-1H-benzo[de]isoquinoline-1-3(2H)-dione) (BND-12) was evaluated using multiparameter cytotoxicity 2 kit by High Content Screening (HCS). The antiproliferative ability of BND-12 was evaluated using MTT assay. BND-12-mediated cell apoptosis was evaluated using HCS. Antitumor effects and systemic toxicity of BND-12 were evaluated in vivo using Kunming male mice.

KEY FINDINGS:

After screening, we found BND-12, a novel naphthalimide derivative, exerted favourable antitumour activity in vitro and in vivo. Our data demonstrated that the cytotoxicity of BND-12 was due to cell apoptosis via the mitochondrial pathway. Interestingly, we demonstrated that BND-12 exerted more potent antitumour activity in subcutaneous xenograft tumour growth, survival time and lung metastasis than amonafide in vivo. Encouragingly, preliminary toxicological evaluation demonstrated that BND-12 had no obvious systemic toxicity at the therapeutic dose, especially haematotoxicity.

CONCLUSIONS:

BND-12 exerted potent effects against HCC in vivo and in vitro, importantly, it had no obvious systemic toxicity at the therapeutic dose.

• Authors: Song-Qiang Xie, Qian Li, Ya-Hong Zhang, Zhan Li, Jin Zhao, Chao-Jie Wang
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 64 Issue 10 Pg. 1483-90 (Oct 2012) ISSN: 2042-7158 [Electronic] England
• PMID: 22943179 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Chemical References

• 6,6-(propane-1,3-diylbis(azanediyl)bis(2-(2-(dimethylamino)ethyl))-1H-benzo(de)isoquinoline-1-3(2H)-dione)
• Antineoplastic Agents
• Naphthalimides
• Organophosphonates
• amonafide
• Adenine

Topics

• Adenine
• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Male
• Mice
• Mitochondria (drug effects, metabolism)
• Naphthalimides (pharmacology, toxicity)
• Neoplasm Metastasis
• Organophosphonates
• Survival Rate
• Toxicity Tests
• Xenograft Model Antitumor Assays