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YC-1, a novel potential anticancer agent, inhibit multidrug-resistant protein via cGMP-dependent pathway

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Summary

The aim of the present study was to evaluate the effect of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1) on multidrug resistance. Expression of human P-glycoprotein was assessed by realtime quantitative RT-PCR and western blot. The efflux function of P-glycoprotein was evaluated by rhodamine 123 accumulation and calcein-AM uptake models. The mechanisms of action of YC-1 on different signaling pathways were studied using series of antagonists and the kinetics was also assessed. Cytotoxicity was evaluated by MTT assay. The results demonstrated that increased intracellular accumulation of rhodamine 123 and increased fluorescence of calcein were observed after YC-1 treatment. Furthermore, increased YC-1 concentration resulted in significant decrease in Vmax while KM remained unchanged suggested that YC-1 acted as a noncompetitive inhibitor of P-glycoprotein. Moreover, the inhibition of Pgp efflux function by YC-1 was significantly reversed by NO synthase inhibitor, L-NAME, the sGC inhibitor, ODQ, the PKG inhibitor, Rp-8-Br-PET-cGMPS, and the PKG inhibitor KT5823. In addition, ERK kinase inhibitor PD98059 also significantly restored YC-1 inhibited Pgp efflux function. These results indicated that YC-1 inhibited Pgp efflux via the NO-cGMP-PKG-ERK signaling pathway through noncompetitive inhibition. The present study revealed that YC-1 could be a good candidate for development as a MDR modulator.

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Abbreviations

MDR:

Multidrug resistance

YC-1:

3-(5_-hydroxymethyl-2_-furyl)-1-benzyl indazole

sGC:

soluble guanylate cyclase

L-NAME:

NG-nitro-L-arginine methyl ester

ODQ:

1H-[1,2,4]oxadiazolo[4,3-α] quinoxalin-1-one

Rp-8-Br-PET-cGMPS:

β-Phenyl-1, N 2-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothioate, Rp-isomer

KT5823:

(8R,9S,11S)-(−)-2-methyl-9-methoxyl-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta9(cde)trinen-1-one

PD98059:

2′-amino-3′-methoxyflavone, NO, nitric oxide

NOS:

Nitric-oxide synthase

PKG:

cGMP-dependent protein kinase

ERK:

Extracellular signal-regulated kinase

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Acknowledgments

We acknowledged Dr. Kazumitsu Ueda (Kyoto University) for providing the human MDR1 cDNA. This work was supported grants from National Science Council of Taiwan (NSC 98-2320-B-039-002).

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Correspondence to Horng-Huei Liou.

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Hung, CC., Liou, HH. YC-1, a novel potential anticancer agent, inhibit multidrug-resistant protein via cGMP-dependent pathway. Invest New Drugs 29, 1337–1346 (2011). https://doi.org/10.1007/s10637-010-9496-1

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