Tumor-selective cytotoxicity of benzo[c]phenanthridine derivatives from Toddalia asiatica Lam.

Abstract

Purpose

To develop a novel anti-cancer drug of low side effect against lung adenocarcinoma, the authors screened the bioresources of Okinawa Island, Japan. The medicinal plant Toddalia asiatica Lam. contained three benzo[c]phenanthridine derivatives: dihydronitidine (DHN), nitidine (NTD) and demethylnitidine (DMN). Of the three derivatives, DHN had been shown to selectively inhibit the growth of cancer cells in our previous study. Because of similar molecular topology of NTD or DMN to DHN, it can be expected that NTD and DMN also show selective cytotoxicity. The aim of the present study was therefore to examine the selective cytotoxicity of these two compounds in vitro and in vivo.

Methods

Benzo[c]phenanthridine derivatives were isolated from T. asiatica Lam., and their chemical structures were identified by interpretation of NMR and MS spectrum. Of the isolated compounds, NTD and DMN were evaluated for cytotoxicity in vitro or in vivo.

Results

NTD as well as DHN selectively reduced the growth of murine and human lung adenocarcinoma in vitro with selective intracellular accumulation. NTD has also been proven to be highly effective in vivo to inhibit the growth of both murine and human lung adenocarcinoma in a subcutaneous xenograft model without any deteriorating side effect. In contrast, DMN had no selective cytotoxicity suggesting that 8-methoxy group of NTD is the critical structural feature for the selective cytotoxicity.

Conclusions

This study thus proves the effectiveness of benzo[c]phenanthridine derivatives as anti-cancer agent in vivo for the first time, and discusses the mechanisms responsible for the selective cytotoxicity.