Planta Med 2006; 72(15): 1353-1358
DOI: 10.1055/s-2006-951708
Original Paper
Pharmacology
© Georg Thieme Verlag KG Stuttgart · New York

The Cytotoxic Effect and the Multidrug Resistance Reversing Action of Lignans from Phyllanthus amarus

Daniela F. P. Leite1 , 2 , 3 , Cândida A. L. Kassuya3 , Tânia L. Mazzuco3 , Aline Silvestre4 , Lucilia V. de Melo4 , Vera L. G. Rehder4 , Vivian M. Rumjanek1 , João B. Calixto3
  • 1Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, RJ, Brazil
  • 2Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, RJ, Brazil
  • 3Departamento de Farmacologia, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil
  • 4Centro Pluri-disciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Universidade Estadual de Campinas, UNICAMP, Campinas, SP, Brazil
Weitere Informationen

Publikationsverlauf

Received: May 10, 2006

Accepted: August 25, 2006

Publikationsdatum:
20. Oktober 2006 (online)

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Abstract

Multidrug resistance (MDR) constitutes the major obstacle to the successful treatment of cancer. In several cancer cells, MDR is thought to be mediated by the super-expression of P-glycoprotein (Pgp). Pgp extrudes drugs from the cells, therefore reducing their cytotoxicity, and its activity inhibition may reverse the MDR phenotype. The present study evaluated the possible cytotoxic effect and MDR reversing properties of the extract and compounds isolated from Phyllanthus amarus. To this purpose, two human leukaemia cell lines were employed: K-562 and its vincristine-resistant counterpart Lucena-1, a Pgp-overexpressing subline. We report here that Lucena-1 was significantly more resistant to the cytotoxicity of P. amarus derivatives: the hexane extract (HE, 100 μg/mL), the lignans-rich fraction (LRF, 100 μg/mL) and the lignans nirtetralin (NIRT, 43.2 μg/mL), niranthin (NIRA, 43 μg/mL) or phyllanthin (PHYLLA, 43 μg/mL) exerted cytotoxic effects on K-562 cells with 40.3, 66.0, 62.0, 61.0 or 24.1 % of cell death, respectively. The cellular toxicity observed on Lucena-1 was 16.3, 40.4, 29.4, 30.2, or 24.8 %, respectively. However, cell treatment with the lignan phyltetralin (PHYLT) up to 41.6 μg/mL had no cytotoxic action on either of the cell lines. P. amarus derivatives were also found to be effective in inhibiting Pgp activity as assessed by rhodamine accumulation in Lucena-1 cells, as were the classical Pgp inhibitors, cyclosporine A (160 nM), PSC-833 (2 μM) and verapamil (5 μM). The lignan NIRT produced the most potent inhibition (EC50 = 29.4 μg/mL) followed by NIRA (44.3 μg/mL), LRF (49.1 μg/mL), PHYLT (99.4 μg/mL), PHYLLA and HE (> 100 μg/mL). Lucena-1 cells were more resistant to daunorubicin-induced cell death (LC50 = 50 μM) than K562 cells (LC50 = 4.95 μM). Of note, the P. amarus derivatives significantly potentiated 5μM daunorubicin-induced cell death in Lucena-1 cells (P < 0.01) but not in K562 cells. After treatment only with P. amarus derivatives (100 μg/mL HE, 30 μg/mL LRF, 12.9 μg/mL NIRA, 43.2 μg/mL NIRT, 43 μg/mL PHYLLA or 41.6 μg/mL PHYLT), the Lucena-1 cellular viability was 83.7, 85.3, 101, 69.7, 75.6 or 88.7 %, respectively, whereas the in the presence of daunorubincin, which was not cytotoxic per se, the cell viability decreased to 42.9, 42.2, 64.2, 35.4, 30.4 or 52.6 %, respectively. Together, these results suggest a potential action of P. amarus derivatives as MDR reversing agents, mainly due to their ability to synergize with the action of conventional chemotherapeutics.

References

Prof. Dr. João Batista Calixto

Departamento de Farmacologia

Universidade Federal de Santa Catarina UFSC

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