engleski

Reversal of multidrug resistance by extract from a marine algae Caulerpa taxifolia

Background and purpose: The multi-drug resistance (MDR) of tumor cells presents a major obstacle in tumor chemotherapy. Most of clinically occurring MDR show increased expression of P170-glycoprotein (Pgp). Agents that inhibit Pgp activity at concentrations with little or no cytotoxic effects may be useful in overcoming MDR in clinical chemotherapy when they are administered in combination with anti-cancer drugs. In this study we have shown that hydrophobic extracts from a marine alga, Caulerpa taxifolia, contain reasonably potent MDR inhibitors. Material and methods: The MDR-inhibitory potential of Caulerpa-extract (CE) was determined by measuring the effect of CE (1) on the accumulation of rhodamine 123 (R123) or calcein AM (CaAM) in NIH 3T3 sensitive (3T3) or resistant, human MDR1 transfected (3T3res), mouse fibroblasts, using a rapid and sensitive fluorescent microplate method ; (2) on the binding of 3H-vincristine onto Pgp, using a modified binding method ; and (3) on vanadate-sensitive verapamil-stimulated ATPase activity of Pgp isolated from Sf9 insect (Spodoptera fugiperda) cells infected with recombinant baculovirus carrying the human MDR1 gene, using a colorimetric method for the determination of inorganic phosphate (Pi). Results: (1) CE and a model MDR-inhibitor, verapamil (VER), caused concentration dependent increase in accumulation of CaAM in 3T3res cells without enhancing CaAM accumulation in 3T3 cells (EC50 for CE was 1.4 mg of dry residue/ml in comparison to 4.8 mg/ml (10 mM) for that of VER). Similarly, CE and VER increased the accumulation of R123 in 3T3res cells (EC50 for CE was 2.6 mg of dry residue/ml, and for VER EC50 was 3.8 mg/ml) ; (2) the potential of CE to compete with VCR for binding sides at Pgp was negligible, in contrast to VER (1.0 mg/0.1 ml, 20 mM) which reduced the binding of 3H-VCR for 61 % and (3) Pgp in reaction medium supplemented with VER (10 mM), coincubated with cyclosporin A (5 mM) or CE (0.25 mg/0.1 ml), blocked the activity of vanadate-sensitive verapamil-stimulated ATPase. Conclusions: The results of these assay systems show that CE appears to contain true MDR-reversing agents, which belongs to a cyclosporin A-like, Pgp-ATPase inhibitory, group of MDR-reversing agents. The data presented here are consistent in indicating that compounds from CE are reasonably potent new candidates for in vivo reversal of MDR in clinical chemotherapy of cancer.

multidrugresistance-inhibitor ; marine alga ; Caulerpa taxifolia extract ; NIH 373 cells ; calcein AM ; rhodamine 123

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