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

• Published in: PloS one Vol. 6; no. 11; p. e27222
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.11.2011; Public Library of Science (PLoS)
• Subjects: ABC transporter; ABC transporters; Aberration; Adenosine Triphosphate - biosynthesis; Anthracyclines; Antineoplastic Agents - pharmacology; ATP; ATP-Binding Cassette Transporters - antagonists & inhibitors; Base Sequence; Biology; Biotechnology; Breast cancer; Cancer; Cancer therapies; Cell Line, Tumor; Cytotoxicity; Daunorubicin; Daunorubicin - pharmacology; Deactivation; DNA Primers; Doxorubicin; Doxorubicin - pharmacology; Drug resistance; Drug therapy; Efflux; Flow Cytometry; Gene expression; Glucose metabolism; Glycolysis; Glycoproteins; Humans; Inactivation; Inhibition; Kinases; Laboratory animals; Leukemia; Liver cancer; Medicine; Metabolism; Mitochondria; Mitoxantrone; Mitoxantrone - pharmacology; Pharmaceutical sciences; Real-Time Polymerase Chain Reaction; Sensitivity; Stem cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027222

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.