Planta Med 2011; 77 - PM180
DOI: 10.1055/s-0031-1282938

Evaluation of diterpenic compounds as inhibitors of multidrug resistance on human colon adenocarcinoma cells

M Reis 1, J Serly 2, AM Madureira 1, N Duarte 1, J Molnar 2, MU Ferreira 1
  • 1Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculdade de Farmácia, Universidade de Lisboa, Av. das Forças Armadas, 1600–083, Lisboa, Portugal
  • 2Department of Medical Microbiology, University of Szeged, H-6720 Szeged, Hungary

One of the most promising strategies for overcoming multidrug resistance (MDR) is to use compounds that can modulate P-glycoprotein (Pgp) and restore the cytotoxicity of anticancer drugs. A large variety of compounds have been shown to be MDR-modulators, and some of them have undergone clinical trials. They are a large chemical and structurally diverse group that includes among others, natural products and their semi-synthetic derivatives. However there are currently no reversal agents clinically available. Therefore, a great need for new reversal agents with higher specificity and efficacy still remains [1].

In previous studies, we have reported the isolation of several macrocyclic lathyrane and jatrophane-type diterpenes, which were found to have a potent inhibitory activity against P-glycoprotein of human MDR1 gene-transfected mouse lymphoma cells [2–4].

The purpose of this work was to study the ability of lathyrane and jatrophane derivatives to modulate the transport activity of P-glycoprotein on human colon adenocarcinoma cell lines (COLO 205 and COLO 320). The reversal of MDR was investigated by flow cytometry, measuring rhodamine-123 accumulation. Several of the compounds tested have shown to be strong Pgp inhibitors. Furthermore, some of these modulators, which presented a significant MDR reversal activity, were assayed, in vitro, for their antiproliferative effects in combination with doxorubicin. Some of the compounds synergistically enhanced the effect of the antitumor drug. According to these results, macrocyclic diterpenes may be valuable as lead compounds for the development of Pgp modulators in different multidrug-resistant cancer cells and to further study their effect in animal experiments.

Keywords: Cancer, multidrug resistance, macrocyclic diterpenes, adenocarcinoma cells

Acknowledgement: This study was supported by FCT, Portugal (project PTDC/QUI-QUI/099815/2008; grant SFRH/BD/72915/2010) and Szeged Foundation for Cancer Research, Hungary

References: 1. Shukla S et al. (2008) Expert Opin Drug Metab Toxicol 4: 205–23

2. Duarte N et al. (2008) Bioorg Med Chem 16: 9323–30.

3. Duarte N et al. (2007) Bioorg Med Chem 15: 546–54.

4. Madureira et al. (2006)J Nat Prod 69: 950–53.