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Biochemistry - Hematology - Oncology

Glycolysis Inhibition Inactivates ABC Transporters to Restore Drug Sensitivity in Malignant Cells
Published: Wednesday, November 02, 2011
Author: Ayako Nakano et al.

by Ayako Nakano, Daisuke Tsuji, Hirokazu Miki, Qu Cui, Salah Mohamed El Sayed, Akishige Ikegame, Asuka Oda, Hiroe Amou, Shingen Nakamura, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Kyoko Takeuchi, Akira Sakai, Shuji Ozaki, Kazuma Okano, Takahiro Nakamura, Kohji Itoh, Toshio Matsumoto, Masahiro Abe

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.