title: Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.
abstract: 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.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakano
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.forename: Qu
authors.initials: Q
authors.lastname: Cui
authors.forename: Salah Mohamed
authors.initials: SM
authors.lastname: El Sayed
authors.forename: Akishige
authors.initials: A
authors.lastname: Ikegame
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.forename: Hiroe
authors.initials: H
authors.lastname: Amou
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.forename: Shiro
authors.initials: S
authors.lastname: Fujii
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Akira
authors.initials: A
authors.lastname: Sakai
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D003630:Daunorubicin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D006019:Glycolysis; D006801:Humans; D008942:Mitoxantrone / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D017931:DNA Primers; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D008942:Mitoxantrone; D003630:Daunorubicin
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