Synthetic 1,4-anthracenediones, which block nucleoside transport and induce DNA fragmentation, retain their cytotoxic efficacy in daunorubicin-resistant HL-60 cell lines.
Anthracene-1,4-dione and 6,7-dichloro-1,4-anthracenedione (code names AQ1 and AQ4, respectively) are cytostatic (IC50: 53 and 110 nM, respectively) and cytotoxic (IC50: 100 and 175 nM, respectively) in wild-type drug-sensitive HL-60-S tumor cells at day 4 in vitro. Therefore, the antitumor effects of these drugs were assessed and compared to those of daunorubicin (DAU) in HL-60-RV and HL-60-R8 tumor cells, which are, respectively, P-glycoprotein-positive and -negative multidrug-resistant (MDR) sublines. In contrast to DAU, which loses its cytostatic [resistance factors (RFs): 30.3-31.8] and cytotoxic (RFs: 48.8-58.1) activities in MDR sublines, AQ1 inhibits cell proliferation (RFs: 0.9-1.3) and cell viability (RFs: 1.4-1.6) as effectively in HL-60-RV and HL-60-R8 as in HL-60-S cells. Similarly, DAU decreases the rate of DNA synthesis less effectively in MDR sublines (RFs: 8.0-13.3) but AQ1 inhibits the incorporation of [3H]thymidine into DNA to the same degree in HL-60-S as in HL-60-RV and HL-60-R8 cells (RFs: 0.9-1.1). In contrast to DAU, which is ineffective, the advantage of AQ1 is its ability to block the cellular transport of purine and pyrimidine nucleosides in HL-60-S cells, an effect which persists in the MDR sublines (RFs: 1.1). AQ4, which mimics to a lesser degree all the antitumor effects of AQ1, except the inhibition of adenosine transport, also retains its effectiveness in MDR sublines (RFs: 1.1-3.1). The peaks of DNA cleavage caused by DAU and AQ1 in HL-60-S cells shift to lower concentrations with increasing times of drug exposure but DAU loses most of its ability to induce DNA fragmentation in MDR sublines, whereas the levels of AQ1-induced DNA cleavage at 16 and 24 h are nearly equivalent in HL-60-S, HL-60-RV and HL-60-R8 cells. Because they not only mimic the antitumor effects of DAU in the nM range but also block nucleoside transport and remain effective in tumor cells that have developed different mechanisms of MDR, AQ1 and AQ4 analogs might be valuable to develop new means of polychemotherapy.
Wu
M
M
Anti-cancer Drug laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan, KS 66506-4901, USA.
Wang
B
B
Perchellet
E M
EM
Sperfslage
B J
BJ
Stephany
H A
HA
Hua
D H
DH
Perchellet
J P
JP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000880:Anthraquinones / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D053938:DNA Fragmentation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D003630:Daunorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009705:Nucleosides; C416442:1,4-anthraquinone; D004247:DNA; D003630:Daunorubicin