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
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
VL - 20
SP - 258
EP - 263
JO - International Immunopharmacology
JF - International Immunopharmacology
SN - 1567-5769
IS - 1
ER -