Induction of poly(ADP-ribose) polymerase-1 cleavage by antitumor triptycene bisquinones in wild-type and daunorubicin-resistant HL-60 cell lines.
Induction of poly(ADP-ribose) polymerase-1 cleavage by antitumor triptycene bisquinones in wild-type and daunorubicin-resistant HL-60 cell lines.
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DOI：
10.1016/s0304-3835(02)00493-7
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发表时间：
2002-12
期刊：
影响因子：
9.7
通讯作者：
Yang Wang;E. Perchellet;M. Tamura;D. Hua;J. Perchellet
中科院分区：
文献类型：
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作者：
Yang Wang;E. Perchellet;M. Tamura;D. Hua;J. Perchellet
与其无活性的母体化合物三蝶烯（代号TT 0）相比，新的合成类似物（TT代号）在体外模拟蒽环醌类抗生素柔红霉素（DAU）在nM范围内的抗肿瘤作用，但具有阻断核苷转运并保留其在多药耐药（MDR）肿瘤细胞中的功效的额外优势。由于TT二醌可通过需要RNA和蛋白质合成以及蛋白酶活性的活性机制在24 h诱导DNA片段化，因此测试了其中最具细胞毒性的TT 24诱导聚（ADP-核糖）聚合酶-1（PARP-1）裂解（细胞凋亡的早期标志物）的能力。在野生型药物敏感性HL-60-S细胞中，PARP-1裂解在2-3 h开始，并在6 h时由1.6 μM浓度的TT 24和DAU最大程度诱导。然而，在MDR HL-60-RV细胞中，4 μM TT 24仍能诱导PARP-1裂解，但4-10 μM DAU不能诱导。PARP-1裂解的幅度可能随着三联结构中醌式环的数量而增加，与TT 0相反，所有先导抗肿瘤TT双醌均具有在HL-60-S细胞中完全诱导PARP-1裂解的能力。1 h脉冲处理足以使TT 24和DAU在6 h时诱导PARP-1裂解。由于TT 24和DAU诱导PARP-1裂解的能力被苄氧羰基-Val-Ala-Asp-氟甲基酮抑制，但不被N-甲苯磺酰基-L-苯丙氨酸氯甲基酮抑制，因此，半胱天冬酶介导的凋亡可能参与了这些醌类抗肿瘤药物诱导HL-60肿瘤细胞系统中6 h PARP-1蛋白水解裂解和24 h DNA核小体间断裂的机制。
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 μM 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 μM TT24 but not by 4–10 μM 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.