Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, Pennsylvania, United States of America.
PLoS One. 2012;7(4):e35104. doi: 10.1371/journal.pone.0035104. Epub 2012 Apr 5.
The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure.
This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain-mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se.
Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.
DNA 烷化剂替莫唑胺（TMZ）被广泛用于治疗人类恶性肿瘤，如神经胶质瘤和黑色素瘤。基于之前的结构-活性研究，我们最近通过合理地将 N-乙基硒氰酸酯引入 TMZ 结构中的酰胺官能团，合成了一种新的 TMZ 硒类似物。
与 TMZ 相比，这种 TMZ-Se 类似物对人神经胶质瘤和黑色素瘤细胞具有更高的细胞毒性，并且在小鼠神经胶质瘤和黑色素瘤异种移植模型中具有更强的肿瘤抑制活性。TMZ-Se 对 TMZ 耐药的神经胶质瘤细胞系也有效。为了探讨 TMZ-Se 优越抗肿瘤活性的机制，我们比较了 TMZ 和 TMZ-Se 对细胞凋亡和自噬的影响。与 TMZ 处理的肿瘤细胞相比，TMZ-Se 处理的肿瘤细胞中细胞凋亡明显增加。与 TMZ 相比，TMZ-Se 还引发了更强的自噬反应，并且抑制自噬部分挽救了 TMZ-Se 诱导的细胞死亡，表明 TMZ-Se 触发的自噬有助于细胞死亡。尽管关键自噬基因 Beclin 1 的 mRNA 水平增加，但 TMZ-Se 处理的细胞中 Beclin 1 蛋白下调。用钙蛋白酶抑制剂挽救 TMZ-Se 处理后 Beclin 1 的减少，钙蛋白酶介导的 Beclin1 降解对自噬没有影响，但促进了 TMZ-Se 处理的细胞凋亡。
我们的研究表明，将硒掺入 TMZ 中可以提高这种化疗药物的效力。
