The novel anthracycline annamycin is not affected by P-glycoprotein- related multidrug resistance: Comparison with idarubicin and doxorubicin in HL-60 leukemia cell lines

Ugo Consoli, Waldemar Priebe, Yi He Ling, Radha Mahadevia, Mark Griffin, Shourong Zhao, Roman Perez-Soler, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

A major factor in limiting the efficacy of anthracyclines is overexpression of the MDR1-encoded p-glycoprotein (p-gp). A new analogue less affected by p-gp is annamycin (ANN), an anthracycline antibiotic with high affinity for lipid membranes and significantly more activity than doxorubicin (DOX). We investigated whether ANN was affected by p-gp-mediated multidrug resistance (MDR) by comparing the cellular accumulation and retention of ANN, idarubicin (IDR), and DOX in the p-gp-negative human leukemia cell lines (HL- 60S) and its DOX-selected p-gp-positive subline (HL-60/DOX) with and without verapamil (VER). As expected, HL-60/DOX cells showed lower DOX uptake than HL-60S cells; coincubation with YEA (10 mmol/L) increased uptake 2.6-fold, restoring it to 100% of uptake in HL-60S cells. IDR uptake increased 1.5- fold in the presence of VER, but ANN was not affected. Coincubation with VER increased DOX retention in HL-60/DOX cells 2.8-fold and IDR retention 1.4- fold; unchanged ANN retention indicated that ANN may overcome p-gp. In the cytotoxicity assay to correlate intracellular anthracycline content with antitumor activity, we found ANN to be less potent than DOX and IDR in sensitive cells, ID50 being the drug concentration that inhibits cell growth by 50%, but its resistance index (RI; ID50 resistant cells divided by ID50 sensitive cells) was lower than that of IDR and DOX (2.6 v 40 and 117.5). Coincubation in the presence of VER resulted in 4.5-fold and 2-fold RI decreases of DOX and IDR, respectively, whereas ANN did not change, further confirming ANN's ability to circumvent p-gp-mediated MDR. Confocal microscopy studies of IDA, ANN, and DOX showed higher intracellular drug compartmentalization for DOX in HL-60/DOX cells incubated in the presence of VER. This study provided evidence that, unlike DOX and IDR, ANN is not affected by p-gp-mediated MDR.

Original languageEnglish (US)
Pages (from-to)633-644
Number of pages12
JournalBlood
Volume88
Issue number2
DOIs
StatePublished - Jul 15 1996
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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