TY - JOUR
T1 - Effect of chemical modification on the ability of pyrrolidinium fullerene to induce apoptosis of cells transformed by JAK2 V617F mutant
AU - Funakoshi-Tago, Megumi
AU - Tsukada, Masaki
AU - Watanabe, Toshiro
AU - Mameda, Yuka
AU - Tago, Kenji
AU - Ohe, Tomoyuki
AU - Nakamura, Shigeo
AU - Mashino, Tadahiko
AU - Kasahara, Tadashi
N1 - Funding Information:
We thank Dr. J. N. Ihle for the retroviral vectors of JAK2 and EpoR. This work was supported in part by grants ( 23790096 , 21590072 ) from MEXT , Takeda Science Foundation , the Uehara Memorial Foundation and Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research. This work was also supported by the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology, Japan ( 25460073 ).
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
KW - ASK1
KW - JAK2
KW - JNK
KW - Myeloproliferative neoplasms
KW - Pyrrolidinium fullerene
KW - V617F mutation
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U2 - 10.1016/j.intimp.2014.02.035
DO - 10.1016/j.intimp.2014.02.035
M3 - Article
C2 - 24631513
AN - SCOPUS:84897461996
SN - 1567-5769
VL - 20
SP - 258
EP - 263
JO - International Immunopharmacology
JF - International Immunopharmacology
IS - 1
ER -