Intracellular doxorubicin concentrations and drug-induced DNA damage in a human colon adenocarcinoma cell line and in a drug-resistant subline

Massimo Broggini, Maria Grandi, Paolo Ubezio, Cristina Geroni, Fernando C. Giuliani, Maurizio D'Incalci

Research output: Contribution to journalArticlepeer-review

Abstract

The mechanisms of resistance to doxorubicin (DX) were investigated using a human colon adenocarcinoma cell line (LoVo) and a subline approximately 30 times less sensitive to doxorubicin. LoVo and LoVo/DX were similar in terms of DNA and protein content, cell volume, duration of S phase and the generation time, and proportion of cycling cells. LoVo/DX showed cross-resistance to other anthracyclines, to vinca alkaloids, epipodophyllotoxin derivatives, 4'-(9-acridinylamino-methanesulfon-m-aniside) and actinomycin D. LoVo/DX was equally sensitive to melphalan and showed collateral sensitivity to cis-platinum and 1-β-d-arabinofuranosylcytosine. On exposing LoVo and LoVo/DX to 1.25 and 40 μg/ml DX respectively, for 4 hr, similar DX intracellular concentrations were reached in the two cell lines. In these treatment conditions protein associated DNA-single strand breaks or DNA-double strand breaks, assessed by alkaline elution methods were only slightly less in LoVo/DX than in LoVo cells. In LoVo/DX cells, however, DNA breaks disappeared very quickly after drug removal whereas they persisted longer in LoVo cells. This persistance is probably related to the much slower DX efflux from LoVo than LoVo/DX. When verapamil was combined with DX it inhibited the rapid DX efflux from LoVo/DX and reversed the resistance in this cell line, but it had no significant activity on LoVo cells. Verapamil also increased DX-induced DNA-single strand breaks and DNA-double strand breaks in LoVo/DX cells, but not in LoVo cells.

Original languageEnglish
Pages (from-to)4423-4431
Number of pages9
JournalBiochemical Pharmacology
Volume37
Issue number23
DOIs
Publication statusPublished - Dec 1 1988

ASJC Scopus subject areas

  • Pharmacology

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