Induction of poly(ADP-ribose) polymerase-1 cleavage by antitumor triptycene bisquinones in wild-type and daunorubicin-resistant HL-60 cell lines.
In contrast to their inactive parent compound triptycene (code name TT0), new synthetic analogs (TT code number) mimic the antitumor effects of the anthracycline quinone antibiotic daunorubicin (DAU) in the nM range in vitro but have the additional advantage of also blocking nucleoside transport and retaining their efficacy in multidrug-resistant (MDR) tumor cells. Since TT bisquinones may induce DNA fragmentation at 24 h by an active mechanism that requires RNA and protein syntheses and protease activities, the most cytotoxic of them, TT24, was tested for its ability to induce poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, an early marker of apoptosis. PARP-1 cleavage starts at 2-3 h and is maximally induced at 6 h by 1.6 microM concentrations of TT24 and DAU in wild-type drug-sensitive HL-60-S cells. However, in MDR HL-60-RV cells, PARP-1 cleavage is still induced by 4 microM TT24 but not by 4-10 microM DAU. The magnitude of PARP-1 cleavage may increase with the number of quinoid rings in the triptych structure and, in contrast to TT0, all lead antitumor TT bisquinones share the ability to fully induce PARP-1 cleavage in HL-60-S cells. A 1 h pulse treatment is sufficient for TT24 and DAU to induce PARP-1 cleavage at 6 h. Since the abilities of TT24 and DAU to induce PARP-1 cleavage are inhibited by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone but not by N-tosyl-L-phenylalanine chloromethyl ketone, caspase-mediated apoptosis may be involved in the mechanism by which these quinone antitumor drugs induce the proteolytic cleavage of PARP-1 at 6 h and the internucleosomal fragmentation of DNA at 24 h in the HL-60 tumor cell system.
Wang
Yang
Y
Anti-Cancer Drug Laboratory, Division of Biology, Ackert Hall, Kansas State University, Manhattan, KS 66506-4901, USA.
Perchellet
Elisabeth M
EM
Tamura
Masafumi
M
Hua
Duy H
DH
Perchellet
Jean Pierre
JP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis*; D011809:Quinones / Q000494:pharmacology*; D000095622:Benzoisochromanequinones
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D003630:Daunorubicin; D011065:Poly(ADP-ribose) Polymerases; D011809:Quinones; C447411:triptycene bisquinone; D000095622:Benzoisochromanequinones