Chih-Hsin Yang1, Yao-Chang Chen, Min-Liang Kuo. 1. Department of Oncology, Cancer Research Center, National Taiwan University Hospital, Medical College, National Taiwan University, Taipei, Taiwan. chjyang@ha.mc.ntu.edu.tw
Abstract
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. MATERIALS AND 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. CONCLUSION: 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.
BACKGROUND:Novobiocin was shown to sensitize cancer cells to etoposide and alkylating agents. Humanbreast 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. MATERIALS AND 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 mitoxantronetoxicity in MCF7/TPT300 cells at a clinically relevant concentration. Novobiocin enhanced cellular accumulation of topotecan and inhibited topotecan efflux in MCF7/TPT300 cells. CONCLUSION:Novobiocin may enhance topotecan and mitoxantronetoxicity in topotecan-resistant breast carcinoma cells. Novobiocin may be useful to reverse topotecan or mitoxantrone resistance in the clinic.
Authors: Amila K Nanayakkara; Courtney A Follit; Gang Chen; Noelle S Williams; Pia D Vogel; John G Wise Journal: Sci Rep Date: 2018-01-17 Impact factor: 4.379