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

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.

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Authors and Affiliations

  1. Center of Molecular Biosciences, University of the Ryukyus, Nishihara, Okinawa, 903-0213, Japan
    Hironori Iwasaki, Takafumi Okabe, Masayuki Shimatani & Hirosuke Oku
  2. Department of Bioscience and Biotechnology, Faculty of Agriculture, University of the Ryukyus, Okinawa, 903-0213, Japan
    Kensaku Takara
  3. Department of Clinical Laboratory Medicine, School of Medicine, University of the Ryukyus Hospital, Uehara 207, Nishihara, Okinawa, 903-0125, Japan
    Takayoshi Toda

Authors

  1. Hironori Iwasaki
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  2. Takafumi Okabe
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  3. Kensaku Takara
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  4. Takayoshi Toda
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  5. Masayuki Shimatani
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  6. Hirosuke Oku
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Corresponding author

Correspondence toHironori Iwasaki.

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Iwasaki, H., Okabe, T., Takara, K. et al. Tumor-selective cytotoxicity of benzo[c]phenanthridine derivatives from Toddalia asiatica Lam..Cancer Chemother Pharmacol 65, 719–726 (2010). https://doi.org/10.1007/s00280-009-1077-7

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