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Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration.
Molecules 2019; 24(18)M

Abstract

Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and its associated transporter anion exchanger AE2 in lung cancer cell line A549. The surface expression of CA12 and AE2 were decreased by Disulfiram treatment with a time-dependent manner. Disulfiram treatment did not alter the expression of Na+-bicarbonate cotransporters, nor did it affect autophagy regulation. The chloride bicarbonate exchanger activity of A549 cells was reduced by Disulfiram treatment in a time-dependent manner without change in the resting pH level. The expression and activity of AE2 and the expression of CA12 were also reduced by Disulfiram treatment in the breast cancer cell line. An invasion assay and cell migration assay revealed that Disulfiram attenuated the invasion and migration of A549 cells. In conclusion, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by Disulfiram treatment in cancer cells provided the molecular evidence supporting the potential of Disulfiram as an anticancer agent.

Authors+Show Affiliations

Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea. snrntlwy1004@gmail.com.Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Korea. dmshin@yuhs.ac.Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, 155 Getbeolro, Yeonsu-gu, Incheon 21999, Korea. minicleo@gachon.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31546841

Citation

Hwang, Soyoung, et al. "Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration." Molecules (Basel, Switzerland), vol. 24, no. 18, 2019.
Hwang S, Shin DM, Hong JH. Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration. Molecules. 2019;24(18).
Hwang, S., Shin, D. M., & Hong, J. H. (2019). Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration. Molecules (Basel, Switzerland), 24(18), doi:10.3390/molecules24183409.
Hwang S, Shin DM, Hong JH. Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration. Molecules. 2019 Sep 19;24(18) PubMed PMID: 31546841.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug Repurposing as an Antitumor Agent: Disulfiram-Mediated Carbonic Anhydrase 12 and Anion Exchanger 2 Modulation to Inhibit Cancer Cell Migration. AU - Hwang,Soyoung, AU - Shin,Dong Min, AU - Hong,Jeong Hee, Y1 - 2019/09/19/ PY - 2019/08/07/received PY - 2019/09/15/revised PY - 2019/09/17/accepted PY - 2019/9/25/entrez PY - 2019/9/25/pubmed PY - 2019/9/25/medline KW - antitumor agent KW - cancer cell migration KW - disulfiram (DSF) KW - drug repurposing JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 18 N2 - Disulfiram has been used in the treatment of alcoholism and exhibits an anti-tumor effect. However, the intracellular mechanism of anti-tumor activity of Disulfiram remains unclear. In this study, we focused on the modulatory role of Disulfiram via oncogenic factor carbonic anhydrase CA12 and its associated transporter anion exchanger AE2 in lung cancer cell line A549. The surface expression of CA12 and AE2 were decreased by Disulfiram treatment with a time-dependent manner. Disulfiram treatment did not alter the expression of Na+-bicarbonate cotransporters, nor did it affect autophagy regulation. The chloride bicarbonate exchanger activity of A549 cells was reduced by Disulfiram treatment in a time-dependent manner without change in the resting pH level. The expression and activity of AE2 and the expression of CA12 were also reduced by Disulfiram treatment in the breast cancer cell line. An invasion assay and cell migration assay revealed that Disulfiram attenuated the invasion and migration of A549 cells. In conclusion, the attenuation of AE2 and its supportive enzyme CA12, and the inhibitory effect on cell migration by Disulfiram treatment in cancer cells provided the molecular evidence supporting the potential of Disulfiram as an anticancer agent. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/31546841/Drug_Repurposing_as_an_Antitumor_Agent:_Disulfiram-Mediated_Carbonic_Anhydrase_12_and_Anion_Exchanger_2_Modulation_to_Inhibit_Cancer_Cell_Migration L2 - http://www.mdpi.com/resolver?pii=molecules24183409 DB - PRIME DP - Unbound Medicine ER -
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