Drug repurposing as an antitumor agent: Disulfiram-mediated carbonic anhydrase 12 and anion exchanger 2 modulation to inhibit cancer cell migration

Soyoung Hwang; Dong Min Shin; Jeong Hee Hong

doi:10.3390/molecules24183409

Drug repurposing as an antitumor agent: Disulfiram-mediated carbonic anhydrase 12 and anion exchanger 2 modulation to inhibit cancer cell migration

Soyoung Hwang, Dong Min Shin, Jeong Hee Hong

Department of Oral Biology

Research output: Contribution to journal › Article › peer-review

16 Citations (Scopus)

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.

Original language	English
Article number	3409
Journal	Molecules
Volume	24
Issue number	18
DOIs	https://doi.org/10.3390/molecules24183409
Publication status	Published - 2019 Sept 19

Bibliographical note

Funding Information:
Funding: This research was funded by by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [NRF-2019R1F1A1046785 (J.H.H.), NRF-2017R1D1A1B03028015 (D.M.S.)] and the grant from the Gachon University Gil Medical Center project [FRD 2018-07 (J.H.H.)].

Publisher Copyright:
© 2019 by the authors.

All Science Journal Classification (ASJC) codes

Analytical Chemistry
Chemistry (miscellaneous)
Molecular Medicine
Pharmaceutical Science
Drug Discovery
Physical and Theoretical Chemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/molecules24183409

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title = "Drug repurposing as an antitumor agent: Disulfiram-mediated carbonic anhydrase 12 and anion exchanger 2 modulation to inhibit cancer cell migration",

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.",

author = "Soyoung Hwang and Shin, {Dong Min} and Hong, {Jeong Hee}",

note = "Funding Information: Funding: This research was funded by by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [NRF-2019R1F1A1046785 (J.H.H.), NRF-2017R1D1A1B03028015 (D.M.S.)] and the grant from the Gachon University Gil Medical Center project [FRD 2018-07 (J.H.H.)]. Publisher Copyright: {\textcopyright} 2019 by the authors.",

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N1 - Funding Information: Funding: This research was funded by by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [NRF-2019R1F1A1046785 (J.H.H.), NRF-2017R1D1A1B03028015 (D.M.S.)] and the grant from the Gachon University Gil Medical Center project [FRD 2018-07 (J.H.H.)]. Publisher Copyright: © 2019 by the authors.

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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.

AB - 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.

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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

Abstract

Bibliographical note

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UN SDGs

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