Novobiocin sensitizes BCRP/MXR/ABCP overexpressing topotecan-resistant human breast carcinoma cells to topotecan and mitoxantrone.
BACKGROUND
Novobiocin was shown to sensitize cancer cells to etoposide and alkylating agents. Human breast carcinoma cells exposed to topotecan (MCF7/TPT300 cells) developed resistance to both mitoxantrone and topotecan. An ATP-binding cassette family protein BCRP/MXR/ABCP was overexpressed in MCF7/TPT300 cells. In addition, topotecan efflux was markedly enhanced in the resistant cells. To investigate the possibility that novobiocin may enhance cytotoxicity in BCRP/MXR/ABCP overexpressing cells, we exposed MCF7/TPT300 cells to novobiocin.


METHODS
Cytotoxicity tests of topotecan and mitoxantrone, as well as topotecan accumulation tests, were performed with or without novobiocin in MCF7/TPT300 cells.


RESULTS
Novobiocin enhances topotecan and mitoxantrone toxicity in MCF7/TPT300 cells at a clinically relevant concentration. Novobiocin enhanced cellular accumulation of topotecan and inhibited topotecan efflux in MCF7/TPT300 cells.


CONCLUSIONS
Novobiocin may enhance topotecan and mitoxantrone toxicity in topotecan-resistant breast carcinoma cells. Novobiocin may be useful to reverse topotecan or mitoxantrone resistance in the clinic.
Yang
Chih-Hsin
CH
Department of Oncology, Cancer Research Center, National Taiwan University Hospital, Medical College, National Taiwan University, Taipei, Taiwan. chjyang@ha.mc.ntu.edu.tw
Chen
Yao-Chang
YC
Kuo
Min-Liang
ML
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D008942:Mitoxantrone / Q000008:administration & dosage / Q000494:pharmacology*; D009363:Neoplasm Proteins; D009675:Novobiocin / Q000008:administration & dosage / Q000494:pharmacology*; D019772:Topotecan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D009363:Neoplasm Proteins; D009675:Novobiocin; D019772:Topotecan; D008942:Mitoxantrone