Anthracenedione derivative 1403P-3 induces apoptosis in KB and KBv200 cells via reactive oxygen species-independent mitochondrial pathway and death receptor pathway
Anthracenedione derivative 1403P-3 induces apoptosis in KB and KBv200 cells via reactive oxygen species-independent mitochondrial pathway and death receptor pathway
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DOI：
10.4161/cbt.6.9.4543
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发表时间：
2007-09
影响因子：
3.6
通讯作者：
Jian-ye Zhang;Hai-Ying Wu;X. Xia;Yong‐ju Liang;Yan-yan Yan-Yan-yan-Yan-3522947;Z. She;Yong‐cheng Lin;L. Fu
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文献类型：
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作者：
Jian-ye Zhang;Hai-Ying Wu;X. Xia;Yong‐ju Liang;Yan-yan Yan-Yan-yan-Yan-3522947;Z. She;Yong‐cheng Lin;L. Fu
蒽二酮衍生物是一种有效的肿瘤细胞毒性药物。本研究对从红树林内生真菌1403号次级代谢产物中分离得到的蒽二酮衍生物1403 P-3的抗癌活性进行了研究。结果表明，1403 P-3不仅对人表皮样癌药敏细胞株KB和多药耐药（MDR）细胞株KBv 200有较强的细胞毒作用，IC_（50）分别为19.66和19.27 μM。Hoechst 33258染色、DNA片段化和聚腺苷二磷酸核糖聚合酶（poly（ADP-ribose）polymerase，PARP）裂解检测证实1403 P-3可诱导KB细胞和KBv 200细胞凋亡。此外，1403 P-3引发的细胞凋亡的特征在于线粒体膜电位（Δ Vm）的丧失、细胞色素c的释放、Bid的裂解以及半胱天冬酶-2、-3、-7、-8和-9的活化。Caspase-8抑制剂Z-IETD-FMK可抑制1403 P-3诱导的Caspase-2活化和Bid裂解。然而，Z-IETD-FMK不抑制1403 P-3引起的caspase-9活化和PARP裂解。1403 P-3对Bcl-2和Bax的表达无明显影响。值得注意的是，1403 P-3减少了KB细胞和KBv 200细胞中活性氧（ROS）的产生。DNA结合实验表明，1403 P-3诱导的细胞凋亡不参与嵌入DNA。综上所述，1403 P-3通过线粒体途径和死亡受体途径诱导KB细胞和KBv 200细胞凋亡。此外，线粒体途径是独立的活性氧和caspase-8的激活。
Anthracenedione derivatives are potent cytotoxic agents to tumour cells. In this study, we investigated the anticancer activities of anthracenedione derivative 1403P-3 separated from the secondary metabolites of the mangrove endophytic fungus No. 1403. Our results demonatrated that 1403P-3 showed potent cytotoxicity not only to human epidermoid carcinoma drug-sensitive parental KB cells but also to multidrug resistant (MDR) KBv200 cells and the IC50 values were 19.66 and 19.27 μM, respectively. Further research indicated that 1403P-3 induced apoptosis in KB cells and KBv200 cells confirmed by Hoechst 33258 staining, detection of DNA fragmentation and cleavage of poly (ADP-ribose) polymerase (PARP). Furthermore, apoptosis triggered by 1403P-3 was characterized by the loss of mitochondrial membrane potential (ΔΨm), release of cytochrome c, cleavage of Bid, and activation of caspases-2, -3, -7, -8 and -9. Z-IETD-FMK, caspase-8 inhibitor could inhibit the activation of caspase-2 and cleavage of Bid induced by 1403P-3. However, activation of caspase-9 and cleavage of PARP caused by 1403P-3 were not inhibited by Z-IETD-FMK. Additionally, 1403P-3 did not influence the expression level of Bcl-2 and Bax. It is noteworthy that 1403P-3 decreased the generation of reactive oxygen species (ROS) in KB cells and KBv200 cells. DNA binding assay exhibited that apoptosis induced by 1403P-3 was not involved in intercalating to DNA. In summary, 1403P-3 induced apoptosis of KB cells and KBv200 cells through mitochondrial pathway and death receptor pathway. Furthermore, the mitochondrial pathway was independent of reactive oxygen species and activation of caspase-8.