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首页> 外文期刊>Advances in enzyme regulation >Screening for inducers of apoptosis in apoptosis-resistant human carcinoma cells.
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Screening for inducers of apoptosis in apoptosis-resistant human carcinoma cells.

机译：筛选抗凋亡人类癌细胞凋亡诱导剂。

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Many anticancer agents are known to induce apoptosis in cultured cells, but human solid tumor cells are often resistant to apoptosis induction. Human pancreatic adenocarcinoma AsPC-1 cells were found to be resistant to apoptosis. So, we screened microbial culture filtrates and synthetic chemicals for their ability to induce apoptosis in AsPC-1 cells. Polyoxypeptin A was isolated from a Streptomyces culture broth as a potent inducer of apoptosis. Its cyclic hexadepsipeptide structure contains a simple but hitherto unreported amino acid, (2S,3R)-3-hydroxy-3-methylproline. Polyoxypeptin A induced early cell death, apoptotic morphology, and internucleosomal DNA fragmentation in AsPC-1 cells at low concentrations. Polyoxypeptin A can induce caspase 3 activation in human T cell leukemia Jurkat cells but not in AsPC-1 cells. The mechanism of apoptosis in AsPC-1 cells has not been elucidated yet. Less toxic derivatives of polyoxypeptin A are being prepared. A macrocyclic lactam called BE-14106 was also isolated from Streptomyces as an inducer of apoptosis in AsPC-1 cells. Histidine-pyridine-histidine-3 (HPH-3) is an oxygen-activating ligand derived from the structure of bleomycin, and it also induced apoptosis in AsPC-1 cells. Induction of apoptosis by HPH-3 was inhibited by zinc and copper ions, indicating that chelation with ferrous ion is responsible for induction of apoptosis, as is chelation by bleomycin to cleave DNA. Bleomycin A2 and its portion having no DNA-binding region, glycopeptide-3(GP-3), did not induce apoptosis in AsPC-1 cells. Thus, among the actions of bleomycin-related compounds, the induction of apoptosis is a unique characteristic of HPH-3.
机译：已知许多抗癌剂可诱导培养细胞的凋亡，但人实体肿瘤细胞通常对凋亡诱导具有抗性。发现人胰腺腺癌AsPC-1细胞对细胞凋亡具有抗性。因此，我们筛选了微生物培养滤液和合成化学物质诱导AsPC-1细胞凋亡的能力。从链霉菌培养液中分离出多氧合肽素A作为有效的凋亡诱导剂。它的环状六肽肽结构包含一个简单但迄今未报道的氨基酸（2S，3R）-3-羟基-3-甲基脯氨酸。在低浓度下，Posoxypeptin A诱导AsPC-1细胞早期细胞死亡，凋亡形态和核小体间DNA断裂。聚氧肽素A可以在人T细胞白血病Jurkat细胞中诱导caspase 3活化，而在AsPC-1细胞中则不能。尚未阐明AsPC-1细胞中的凋亡机制。正在制备毒性较小的聚氧肽原A衍生物。还从链霉菌中分离出称为BE-14106的大环内酰胺作为AsPC-1细胞凋亡的诱导剂。组氨酸-吡啶-组氨酸-3（HPH-3）是源自博来霉素结构的氧激活配体，它还诱导AsPC-1细胞凋亡。 HPH-3对细胞凋亡的诱导被锌和铜离子抑制，这表明与亚铁离子的螯合可诱导细胞凋亡，博莱霉素对DNA的螯合也是如此。博来霉素A2及其不具有DNA结合区的部分糖肽3（GP-3）在AsPC-1细胞中不诱导凋亡。因此，在博来霉素相关化合物的作用中，凋亡的诱导是HPH-3的独特特征。

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