Sodium azulene sulfonate reverses multidrug resistance in K562/A02 cells

Ziwei Wang; Na Zhou; Jianqi Zhao; Xin Zhang

doi:10.14715/cmb/2019.65.7.18

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Vol. 65 No. 7: Issue 7

Issue Published : October 14, 2019

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Sodium azulene sulfonate reverses multidrug resistance in K562/A02 cells

https://doi.org/10.14715/cmb/2019.65.7.18

Ziwei Wang

Department of Pharmacy, School and Hospital of Stomatology, Jilin University, China

Na Zhou

Department of Pharmacy, School and Hospital of Stomatology, Jilin University, China

Jianqi Zhao

Department of Pharmacy, First Hospital of Jilin University, Changchun City, China

Xin Zhang

Department of Pharmacy, First Hospital of Jilin University, Changchun City, China

Corresponding Author(s) : Xin Zhang

zjmcy3@163.com

Cellular and Molecular Biology, Vol. 65 No. 7: Issue 7
Article Published : September 30, 2019

Abstract

Overexpression of p-glycoprotein (p-gp) is the main cause of multidrug resistance and chemotherapy failure in leukemia. Sodium azulene sulfonate (SAS) was used to reverse the multidrug resistance of human leukemia adriamycin-resistant strain K562/A02, and the underlying mechanism was investigated. Human leukemia cell line K562 and drug-resistant cell line K562/A02 in logarithmic phase were used in this study. After 48 hours of treatment of K562/A02 cells with SAS, the intrinsic cytotoxicity of chlorogenic acid and its sensitivity to adriamycin (ADM) were determined with MTT assay. The degree of reversal was calculated. Using ADM accumulation and rhodamine 123 efflux experiments, the average fluorescence intensity of ADM and rhodamine 123 (Rh123) in chlorogenic acid-treated K562/A02 cells was determined flow cytometrically. The expressions of p-gp, t-Akt and p-Akt in K562/A02 cells were assayed using Western blotting. SAS had almost no cytotoxic effect, and the degree of inhibition was only about 20% at the highest concentration of 100 mu-M. The EC50 of MDR reversal by SAS was in the nano range (539±37nM), and it had a high selectivity index for normal cells (>185). The accumulation of ADM in drug-resistant cells was increased significantly after treatment with 1 and 5 mu-M SAS, while the efflux of Rh123 was significantly inhibited, suggesting that SAS reversed MDR by inhibiting p-gp function. Western blotting experiments showed that SAS downregulated the expression of p-gp by inhibiting PI3K/Akt signaling pathway. This contributed to the reversal of drug resistance.SAS effectively reverses multidrug resistance in vitro by inhibiting the function of p-gp in K562/A02 cells, through a mechanism involving downregulation of the P13K/Akt signaling pathway. Therefore, SAS may be a potential candidate drug for reversal of MDR.

Keywords

Sodium azulene sulfonate Multidrug resistance p-glycoprotein Adriamycin Reversal activity.

Wang, Z., Zhou, N., Zhao, J., & Zhang, X. (2019). Sodium azulene sulfonate reverses multidrug resistance in K562/A02 cells. Cellular and Molecular Biology, 65(7), 105–110. https://doi.org/10.14715/cmb/2019.65.7.18

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References

Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol 2017; 10: 93.
Yan Y, Liang H, Xie L, He Y, Li M, Li R, et al. Association of MDR1 G2677T polymorphism and leukemia risk: evidence from a meta-analysis. Tumour Biol 2014; 35: 2191.
Rebucci M, Michiels C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 2013; 85: 1219-1226.
Gillet JP, Gottesman MM. Mechanisms of Multidrug Resistance in Cancer. Methods Mol Biol 2010; 596: 47-76.
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Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007; 12: 927-941.
Morad SAF, Davis TS, MacDougall MR, Tan SF, Feith DJ, Desai DH, et al. Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer. Biochem Pharmacol 2017; 130: 21-33.
Yanagisawa T, Wakabayashi S, Tomiyama T, Yasunami M, Takase KJC, Bulletin P. Synthesis and anti-ulcer activities of sodium alkylazulene sulfonates. Chem Pharm Bull (Tokyo) 1988; 36: 641-647.
Sakai H, Misawa M. Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats. Basic Clin Pharmacol Toxicol 2005; 96: 54-59.
Nihei S, Sato J, Komatsu H, Ishida K, Kimura T, Tomita T, et al. The efficacy of sodium azulene sulfonate L-glutamine for managing chemotherapy-induced oral mucositis in cancer patients: a prospective comparative study. J Pharm Health Care Sci 2018; 4: 20.
Yamamoto T, Yamaoka T, Yoshida Y, Shin K, Aonuma H, Tanaka T. Anti-inflammatory, stable aqueous preparation comprising azulene sodium sulfonate and polyhydric alcohol. 1995.
Varma MV, Ashokraj Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 2003; 48: 347-359.
Li YS, Zhao DS, Liu XY, Liao YX, Jin HW, Song GP, et al. Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-glycoprotein inhibitors for Doxorubicin resistance in MCF-7/ADR cell. Eur J Med Chem 2018; 151: 546-556.
Chan KF, Wong IL, Kan JW, Yan CS, Chow LM, Chan TH. Amine Linked Flavonoid Dimers as Modulators for P-Glycoprotein-Based Multidrug Resistance: Structure–Activity Relationship and Mechanism of Modulation. J Med Chem 2012; 55: 1999-2014.
Iyer VV, Priya PY, Kangeyavelu J. Effects of increased accumulation of doxorubicin due to emodin on efflux transporter and LRP1 expression in lung adenocarcinoma and colorectal carcinoma cells. Mol Cell Biochem 2018; 449: 1-14.
Hu R, Gao J, Rozimamat R, Aisa HA. Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance. Eur J Med Chem 2018; 146: 157-170.
Callaghan R, George AM, Kerr ID. 8.8 Molecular Aspects of the Translocation Process by ABC Proteins. Compr Biophys 2012; 12:145-173.
Stouch TR, Gudmundsson O. Progress in understanding the structure–activity relationships of P-glycoprotein. Adv Drug Deliv Rev 2002; 54: 315-328.
And YR, Sharom FJ. The Membrane Lipid Environment Modulates Drug Interactions with the P-Glycoprotein Multidrug Transporter" . Biochemistry 1999; 38: 6887.
Robert J, Jarry C. Multidrug resistance reversal agents. Cheminform 2004; 35: 4805-4817.
Li H, Hui L, Xu W, Shen H, Chen Q, Long L, et al. Modulation of P-glycoprotein expression by triptolide in adriamycin-resistant K562/A02 cells. Oncol Lett 2012; 3: 485-489.
Bai Z, Gao M, Zhang H, Guan Q, Xu J, Li Y, et al. BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe. Cancer Lett 2017; 402: 81-92.
Hu Y, Qin X, Cao H, Yu S, Feng J. Reversal effects of local anesthetics on P-glycoprotein-mediated cancer multidrug resistance. Anticancer Drugs 2017; 28: 243-249.
Han LW, Gao C, Mao Q. An update on expression and function of p-gp/abcb1 and bcrp/abcg2 in the placenta and fetus. Expert Opin Drug Metab Toxicol 2018; 14: 817-829.
Ma H, Cheng L, Hao K, Li Y, Song X, Zhou H, et al. Reversal Effect of ST6GAL 1 on Multidrug Resistance in Human Leukemia by Regulating the PI3K/Akt Pathway and the Expression of P-gp and MRP1. PloS one 2014; 9: 85113.
Lin X, Zhang X, Wang Q, Li J, Zhang P, Zhao M, et al. Perifosine downregulates MDR1 gene expression and reverses multidrug-resistant phenotype by inhibiting PI3K/Akt/NF-ÎºB signaling pathway in a human breast cancer cell line. Neoplasma 2012; 59: 248-256.

References

Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol 2017; 10: 93.

Yan Y, Liang H, Xie L, He Y, Li M, Li R, et al. Association of MDR1 G2677T polymorphism and leukemia risk: evidence from a meta-analysis. Tumour Biol 2014; 35: 2191.

Rebucci M, Michiels C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 2013; 85: 1219-1226.

Gillet JP, Gottesman MM. Mechanisms of Multidrug Resistance in Cancer. Methods Mol Biol 2010; 596: 47-76.

Ford RC, Kamis AB, Kerr ID, Callaghan R. The ABC Transporters: Structural Insights into Drug Transport. Wiley"VCH Verlag GmbH & Co. KGaA 2010; 12: 7.

Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007; 12: 927-941.

Morad SAF, Davis TS, MacDougall MR, Tan SF, Feith DJ, Desai DH, et al. Role of P-glycoprotein inhibitors in ceramide-based therapeutics for treatment of cancer. Biochem Pharmacol 2017; 130: 21-33.

Yanagisawa T, Wakabayashi S, Tomiyama T, Yasunami M, Takase KJC, Bulletin P. Synthesis and anti-ulcer activities of sodium alkylazulene sulfonates. Chem Pharm Bull (Tokyo) 1988; 36: 641-647.

Sakai H, Misawa M. Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats. Basic Clin Pharmacol Toxicol 2005; 96: 54-59.

Nihei S, Sato J, Komatsu H, Ishida K, Kimura T, Tomita T, et al. The efficacy of sodium azulene sulfonate L-glutamine for managing chemotherapy-induced oral mucositis in cancer patients: a prospective comparative study. J Pharm Health Care Sci 2018; 4: 20.

Yamamoto T, Yamaoka T, Yoshida Y, Shin K, Aonuma H, Tanaka T. Anti-inflammatory, stable aqueous preparation comprising azulene sodium sulfonate and polyhydric alcohol. 1995.

Varma MV, Ashokraj Y, Dey CS, Panchagnula R. P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement. Pharmacol Res 2003; 48: 347-359.

Li YS, Zhao DS, Liu XY, Liao YX, Jin HW, Song GP, et al. Synthesis and biological evaluation of 2,5-disubstituted furan derivatives as P-glycoprotein inhibitors for Doxorubicin resistance in MCF-7/ADR cell. Eur J Med Chem 2018; 151: 546-556.

Chan KF, Wong IL, Kan JW, Yan CS, Chow LM, Chan TH. Amine Linked Flavonoid Dimers as Modulators for P-Glycoprotein-Based Multidrug Resistance: Structure–Activity Relationship and Mechanism of Modulation. J Med Chem 2012; 55: 1999-2014.

Iyer VV, Priya PY, Kangeyavelu J. Effects of increased accumulation of doxorubicin due to emodin on efflux transporter and LRP1 expression in lung adenocarcinoma and colorectal carcinoma cells. Mol Cell Biochem 2018; 449: 1-14.

Hu R, Gao J, Rozimamat R, Aisa HA. Jatrophane diterpenoids from Euphorbia sororia as potent modulators against P-glycoprotein-based multidrug resistance. Eur J Med Chem 2018; 146: 157-170.

Callaghan R, George AM, Kerr ID. 8.8 Molecular Aspects of the Translocation Process by ABC Proteins. Compr Biophys 2012; 12:145-173.

Stouch TR, Gudmundsson O. Progress in understanding the structure–activity relationships of P-glycoprotein. Adv Drug Deliv Rev 2002; 54: 315-328.

And YR, Sharom FJ. The Membrane Lipid Environment Modulates Drug Interactions with the P-Glycoprotein Multidrug Transporter" . Biochemistry 1999; 38: 6887.

Robert J, Jarry C. Multidrug resistance reversal agents. Cheminform 2004; 35: 4805-4817.

Li H, Hui L, Xu W, Shen H, Chen Q, Long L, et al. Modulation of P-glycoprotein expression by triptolide in adriamycin-resistant K562/A02 cells. Oncol Lett 2012; 3: 485-489.

Bai Z, Gao M, Zhang H, Guan Q, Xu J, Li Y, et al. BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe. Cancer Lett 2017; 402: 81-92.

Hu Y, Qin X, Cao H, Yu S, Feng J. Reversal effects of local anesthetics on P-glycoprotein-mediated cancer multidrug resistance. Anticancer Drugs 2017; 28: 243-249.

Han LW, Gao C, Mao Q. An update on expression and function of p-gp/abcb1 and bcrp/abcg2 in the placenta and fetus. Expert Opin Drug Metab Toxicol 2018; 14: 817-829.

Ma H, Cheng L, Hao K, Li Y, Song X, Zhou H, et al. Reversal Effect of ST6GAL 1 on Multidrug Resistance in Human Leukemia by Regulating the PI3K/Akt Pathway and the Expression of P-gp and MRP1. PloS one 2014; 9: 85113.

Lin X, Zhang X, Wang Q, Li J, Zhang P, Zhao M, et al. Perifosine downregulates MDR1 gene expression and reverses multidrug-resistant phenotype by inhibiting PI3K/Akt/NF-ÎºB signaling pathway in a human breast cancer cell line. Neoplasma 2012; 59: 248-256.

Author biographies is not available.