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Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells

Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC tra...

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Autores principales: Nakano, Ayako, Tsuji, Daisuke, Miki, Hirokazu, Cui, Qu, Sayed, Salah Mohamed El, Ikegame, Akishige, Oda, Asuka, Amou, Hiroe, Nakamura, Shingen, Harada, Takeshi, Fujii, Shiro, Kagawa, Kumiko, Takeuchi, Kyoko, Sakai, Akira, Ozaki, Shuji, Okano, Kazuma, Nakamura, Takahiro, Itoh, Kohji, Matsumoto, Toshio, Abe, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206937/
https://www.ncbi.nlm.nih.gov/pubmed/22073292
http://dx.doi.org/10.1371/journal.pone.0027222
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author Nakano, Ayako
Tsuji, Daisuke
Miki, Hirokazu
Cui, Qu
Sayed, Salah Mohamed El
Ikegame, Akishige
Oda, Asuka
Amou, Hiroe
Nakamura, Shingen
Harada, Takeshi
Fujii, Shiro
Kagawa, Kumiko
Takeuchi, Kyoko
Sakai, Akira
Ozaki, Shuji
Okano, Kazuma
Nakamura, Takahiro
Itoh, Kohji
Matsumoto, Toshio
Abe, Masahiro
author_facet Nakano, Ayako
Tsuji, Daisuke
Miki, Hirokazu
Cui, Qu
Sayed, Salah Mohamed El
Ikegame, Akishige
Oda, Asuka
Amou, Hiroe
Nakamura, Shingen
Harada, Takeshi
Fujii, Shiro
Kagawa, Kumiko
Takeuchi, Kyoko
Sakai, Akira
Ozaki, Shuji
Okano, Kazuma
Nakamura, Takahiro
Itoh, Kohji
Matsumoto, Toshio
Abe, Masahiro
author_sort Nakano, Ayako
collection PubMed
description Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2), KG-1 (ABCB1) and HepG2 cells (ABCB1 and ABCG2). Interestingly, although side population (SP) cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.
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spelling pubmed-32069372011-11-09 Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells Nakano, Ayako Tsuji, Daisuke Miki, Hirokazu Cui, Qu Sayed, Salah Mohamed El Ikegame, Akishige Oda, Asuka Amou, Hiroe Nakamura, Shingen Harada, Takeshi Fujii, Shiro Kagawa, Kumiko Takeuchi, Kyoko Sakai, Akira Ozaki, Shuji Okano, Kazuma Nakamura, Takahiro Itoh, Kohji Matsumoto, Toshio Abe, Masahiro PLoS One Research Article Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC) transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA) suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2), KG-1 (ABCB1) and HepG2 cells (ABCB1 and ABCG2). Interestingly, although side population (SP) cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells. Public Library of Science 2011-11-02 /pmc/articles/PMC3206937/ /pubmed/22073292 http://dx.doi.org/10.1371/journal.pone.0027222 Text en Nakano et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Nakano, Ayako
Tsuji, Daisuke
Miki, Hirokazu
Cui, Qu
Sayed, Salah Mohamed El
Ikegame, Akishige
Oda, Asuka
Amou, Hiroe
Nakamura, Shingen
Harada, Takeshi
Fujii, Shiro
Kagawa, Kumiko
Takeuchi, Kyoko
Sakai, Akira
Ozaki, Shuji
Okano, Kazuma
Nakamura, Takahiro
Itoh, Kohji
Matsumoto, Toshio
Abe, Masahiro
Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
title Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
title_full Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
title_fullStr Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
title_full_unstemmed Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
title_short Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
title_sort glycolysis inhibition inactivates abc transporters to restore drug sensitivity in malignant cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206937/
https://www.ncbi.nlm.nih.gov/pubmed/22073292
http://dx.doi.org/10.1371/journal.pone.0027222
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