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01-04-2012 | Original Article

Increased cellular accumulation and distribution of amrubicin contribute to its activity in anthracycline-resistant cancer cells

Authors: Vidya Mamidipudi, Tao Shi, Helen Brady, Sekhar Surapaneni, Rajesh Chopra, Sharon L. Aukerman, Carla Heise, Victoria Sung

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2012

Abstract

Purpose

Multi-drug resistance and cumulative cardiotoxicity are major limitations for the clinical use of anthracyclines. Here, we evaluated and compared the cross-resistance of amrubicin, a third-generation synthetic anthracycline and potent topoisomerase (topo)-II inhibitor with little or no observed cardiotoxicity to other anthracyclines and the topo-II inhibitor etoposide in drug-resistant tumor models in order to elucidate its potential mechanisms of action.

Methods

Amrubicin activity was assessed in multi-drug-resistant cell lines and human tumor explants using cytotoxicity assays, confocal microscopy, fluorescence time-lapse imaging, flow cytometry, immunoblotting, and gene expression profiling techniques.

Results

We demonstrate that both doxorubicin-resistant tumor cell lines and several drug-resistant human ovarian and breast tumor explants retain sensitivity to amrubicin. In addition, we observed similar levels of amrubicin uptake and accumulation in doxorubicin-sensitive versus doxorubicin-resistant cell lines. Although amrubicin is a weak P-glycoprotein substrate, transport and retention of amrubicin were not solely modulated by P-glycoprotein in the resistant cell lines overexpressing drug efflux pumps. The cellular retention of amrubicin is likely to be a result of rapid influx due to its high intrinsic permeability and lipophilic properties, and this may explain why amrubicin overcomes pleiotropic drug resistance. Consistent with drug accumulation studies, amrubicin induced DNA damage, G₂–M cell cycle arrest, and apoptosis in both doxorubicin-sensitive and doxorubicin-resistant lines. Using gene expression profiling studies, several classes of genes were significantly and uniquely regulated following amrubicin, but not doxorubicin or etoposide, treatment.

Conclusions

Amrubicin appears to have a distinct mode of action that overcomes typical anthracycline resistance mechanisms. Therefore, amrubicin may be useful in the treatment of anthracycline-refractory or anthracycline-resistant tumors.

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Title: Increased cellular accumulation and distribution of amrubicin contribute to its activity in anthracycline-resistant cancer cells
Authors: Vidya Mamidipudi
Tao Shi
Helen Brady
Sekhar Surapaneni
Rajesh Chopra
Sharon L. Aukerman
Carla Heise
Victoria Sung
Publication date: 01-04-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 4/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1782-x

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