The disaccharide moiety of bleomycin facilitates uptake by cancer cells.
The disaccharide moiety of bleomycin facilitates uptake by cancer cells.
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DOI：
10.1021/ja507255g
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发表时间：
2014-10-01
影响因子：
15
通讯作者：
Hecht, Sidney M.
中科院分区：
文献类型：
--
作者：
Schroeder, Benjamin R.;Ghare, M. Imran;Bhattacharya, Chandrabali;Paul, Rakesh;Yu, Zhiqiang;Zaleski, Paul A.;Bozeman, Trevor C.;Rishel, Michael J.;Hecht, Sidney M.
二糖部分负责博来霉素（BLM）的肿瘤细胞靶向性质。虽然糖苷配基（去糖博来霉素）以与博来霉素大致相同的方式介导DNA切割，但与BLM相比，其表现出降低的细胞毒性。这些结果表明，BLM可能是模块化的性质，包括肿瘤寻求和杀肿瘤结构域。为了探索这种可能性，制备BLM类似物，其中二糖部分在新的位置，即通过苏氨酸部分或C-末端取代基连接到去糖博来霉素。将类似物与BLM和deglycoBLM进行DNA切割、癌细胞摄取和细胞毒活性的比较。BLM在超螺旋质粒DNA松弛中比deglycoBLM更有效，而在苏氨酸上具有二糖的类似物比deglycoBLM活性低，并且含有C-末端二糖的类似物稍微更有效。虽然具有普通的DNA切割效力，这两个糖基化的类似物培养的DU 145前列腺癌细胞比deglycoBLM的细胞毒性。在成像实验中使用染料标记的细胞毒性BLM糖苷配基的缀合物来确定细胞摄取的程度。内化效率的等级顺序与它们对DU 145细胞的细胞毒性的顺序相同。这些发现确立了BLM二糖在肿瘤靶向/摄取中的作用，并表明二糖部分可能能够将其他细胞毒素递送至癌细胞。虽然负责肿瘤细胞选择性摄取BLM二糖的机制尚未建立，但数据表明，癌细胞中糖酵解的代谢转变可能为选择性内化提供了载体。
The disaccharide moiety is responsible for the tumor cell targeting properties of bleomycin (BLM). While the aglycon (deglycobleomycin) mediates DNA cleavage in much the same fashion as bleomycin, it exhibits diminished cytotoxicity in comparison to BLM. These findings suggested that BLM might be modular in nature, composed of tumor-seeking and tumoricidal domains. To explore this possibility, BLM analogues were prepared in which the disaccharide moiety was attached to deglycobleomycin at novel positions, namely, via the threonine moiety or C-terminal substituent. The analogues were compared with BLM and deglycoBLM for DNA cleavage, cancer cell uptake, and cytotoxic activity. BLM is more potent than deglycoBLM in supercoiled plasmid DNA relaxation, while the analogue having the disaccharide on threonine was less active than deglycoBLM and the analogue containing the C-terminal disaccharide was slightly more potent. While having unexceptional DNA cleavage potencies, both glycosylated analogues were more cytotoxic to cultured DU145 prostate cancer cells than deglycoBLM. Dye-labeled conjugates of the cytotoxic BLM aglycons were used in imaging experiments to determine the extent of cell uptake. The rank order of internalization efficiencies was the same as their order of cytotoxicities toward DU145 cells. These findings establish a role for the BLM disaccharide in tumor targeting/uptake and suggest that the disaccharide moiety may be capable of delivering other cytotoxins to cancer cells. While the mechanism responsible for uptake of the BLM disaccharide selectively by tumor cells has not yet been established, data are presented which suggest that the metabolic shift to glycolysis in cancer cells may provide the vehicle for selective internalization.
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影响因子：
4.1
作者：
Afzal, I;Cunningham, P;Naftalin, RJ
通讯作者：
Naftalin, RJ
影响因子：
19.7
作者：
BEKERMAN, C;MORAN, EM;GOTTSCHALK, A
通讯作者：
GOTTSCHALK, A
影响因子：
3.6
作者：
Bodner, R;Marcellino, BK;Rojas, CM
通讯作者：
Rojas, CM
影响因子：
2.9
作者：
Bhattacharya C;Yu Z;Rishel MJ;Hecht SM
通讯作者：
Hecht SM
影响因子：
15
作者：
Duerfeldt AS;Boger DL
通讯作者：
Boger DL