کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5832859 | 1122610 | 2014 | 6 صفحه PDF | دانلود رایگان |
- Pyrrolidinium fullerene induces apoptosis of cells transformed by the JAK2 mutant.
- Pyrrolidinium fullerene inhibits the ASK1-MKK4/7-JNK pathway.
- Introduction of butyl group improves the ability of fullerene to induce apoptosis.
- Introduction of butyl group to fullerene potently inhibits the ASK1-MKK4/7-JNK pathway.
JAK2 V617F mutant, a gene responsible for human myeloproliferative neoplasms (MPNs), causes not only cellular transformation but also resistance to various anti-cancer drugs. We previously reported that pyrrolidinium fullerene markedly induced the apoptosis of JAK2 V617F mutant-induced transformed cells through the reduction of apoptosis signal-regulating kinase 1 (ASK1), following inhibition of the c-Jun N-terminal kinase (JNK) pathway. In the current study, we found that the replacement of the 2-hydrogen atom (H) or N-methyl group (CH3) by the butyl group (C4C9) caused the more than 3-fold potent cytotoxic effects on cells transformed by the JAK2 V617F mutant. Strikingly, these chemical modification of pyrrolidinium fullerene resulted in more marked reduction of ASK1 protein and a more potent inhibitory effect on the JNK signaling cascade. On the other hand, when modified with a longer alkyl group, the derivatives lacked their cytotoxicity. These observations clearly indicate that the modification of pyrrolidinium fullerene with a suitable length of alkyl group such as butyl group enhances its apoptotic effect through inhibition of the ASK1-MKK4/7-JNK pathway.
Journal: International Immunopharmacology - Volume 20, Issue 1, May 2014, Pages 258-263