Quinone isomers of the WS-5995 antibiotics: synthetic antitumor agents that inhibit macromolecule synthesis, block nucleoside transport, induce DNA fragmentation, and decrease the growth and viability of L1210 leukemic cells more effectively than ellagic acid and genistein in vitro.
Antibiotic WS-5995A (code name J4) and two of its synthetic analogs, o-quinone J1 and model p-quinone J7, which show some structural similarity with both ellagic acid (EA) and genistein (GEN), were compared for their antileukemic activity in L1210 cells in vitro. Overall, J4 is more cytostatic and cytotoxic than J1 and J7, suggesting that methyl and methoxy substitutions, a p-quinone moiety, and a hydrogen bonding phenolic group may enhance the antitumor potential of these naphthoquinone lactones, which are all more potent than EA and GEN. For instance, the lead compound J4 inhibits tumor cell proliferation and viability at day 4 (IC(50): 0.24--0.65 microM) more effectively than EA (IC(50): 5--6 microM) and GEN (IC(50): 7 microM). Since J4 does not increase but rather decreases the mitotic index of L1210 cells at 24 h, it is not an antitubulin drug but might arrest early stages of cell cycle progression like EA and GEN. A 1.5- to 3-h pretreatment with J4 is sufficient to inhibit the rates of DNA, RNA and protein syntheses (IC(50): 2.0--2.5 microM) determined over 30- to 60-min periods of pulse-labeling in L1210 cells in vitro, whereas EA (IC(50): 20-130 microM) and GEN (IC(50): 40--115 microM) are less effective against macromolecule synthesis. In contrast to 156 microM EA, which is inactive, a 15-min pretreatment with 10--25 microM J4 has the advantage of also inhibiting the cellular transport of both purine and pyrimidine nucleosides over a 30 s period in vitro, an effect which can be mimicked by 156 microM GEN. Hence, the WS-5995 analogs and GEN may prevent the incorporation of [(3)H]adenosine and [(3)H]thymidine into DNA because they rapidly block the uptake of these nucleosides by the tumor cells. After 24 h, the concentration-dependent induction of DNA cleavage by J4 peaks at 10 microM and declines at 25 microM, whereas EA and GEN are ineffective at 10 microM but maximally stimulate DNA cleavage at 62.5 microM. Like EA and GEN, the mechanism by which J4 induces DNA fragmentation is inhibited by actinomycin D, cycloheximide, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, N-tosyl-L-phenylalanine chloromethyl ketone and ZnSO(4), suggesting that J4 triggers apoptosis by caspase and endonuclease activation. Because they are more potent than EA and GEN, and affect both nucleoside transport and DNA cleavage, the WS-5995 antitumor antibiotics might be valuable in polychemotherapy to potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells.
Perchellet
E M
EM
Anti-Cancer Drug Laboratory, Kansas State University, Division of Biology, Ackert Hall, Manhattan, KS 66506-4901, USA.
Sperfslage
B J
BJ
Qabaja
G
G
Jones
G B
GB
Perchellet
J P
JP
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003374:Coumarins / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D004610:Ellagic Acid / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D007536:Isomerism; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008938:Mitosis / Q000187:drug effects*; D008940:Mitotic Index; D009363:Neoplasm Proteins / Q000187:drug effects; D011809:Quinones; D012334:RNA, Neoplasm / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D003374:Coumarins; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011809:Quinones; D012334:RNA, Neoplasm; D004610:Ellagic Acid; C027838:WS-5995 A; D019833:Genistein