Abstract
Multidrug resistance (MDR) is a major obstacle to the successful chemotherapy of solid tumors. We compared the resistance of the most popular solid tumors, breast adenocarcinoma (MCF-7 cell line) and nonsmall cell lung (A549 cell line) hepatocellular liver carcinoma (HepG2 cells), to aclarubicin (ACL) and doxorubicin (DOX). This research aimed at determining the relation between the toxicity of ACL and DOX, their cell accumulation, and then effect on P-glycoprotein functionality. ACL is more cytotoxic for tumor cells compared to DOX. The intracellular concentration of drugs in cancer cells was dependent on the dose of the drugs and the time of incubation. The P-gp inhibitor Verapamil (V) increased DOX accumulation in all tested cell lines. By contrast, the intracellular level of ACL was not affected by this modifying agent. The assessment of the uptake of 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide (JC-1) or Rhodamine 123 (R123) allows the evaluation of the different influence of drugs on P-gp activity which is in agreement with the estimation of expression measured by MDR-1 shift assay. These data suggest that ACL is less P-gp dependent than DOX and consequently may be used in a clinical setting to increase treatment efficacy in resistant human tumors.
Highlights
Anthracyclines are potent anticancer agents which have been used in the treatment of acute leukemias, Hodgkin’s disease, sarcomas, and solid tumors
We aimed to investigate how far aclarubicin weakens the function of the P-gp transport system and what is the relation between the toxicity of this anthracycline and P glycoprotein functionality after drug treatment
The growth inhibitory effect of doxorubicin and aclarubicin against A549, HepG2, and MCF7 and human cancer cells is shown in Figure 1, which presents the viability curves of analyzed solid tumor cell lines treated with ACL or DOX
Summary
Anthracyclines are potent anticancer agents which have been used in the treatment of acute leukemias, Hodgkin’s disease, sarcomas, and solid tumors. Despite their generalized application for more than 40 years, the mechanisms of anthracyclines cytotoxicity have long been a matter of controversy. The therapeutic activity of anthracyclines is lower that in the case when tumor cells are resistant to anticancer drugs application. One of the most important cellular transporters is Pgp [5, 6] This protein was first discovered in mammalian cells that had been selected for resistance to the drug [7]. Our study suggests that ACL is a poor substrate of this transporter
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