Effect of chemical modification on the ability of pyrrolidinium fullerene to induce apoptosis of cells transformed by JAK2 V617F mutant

Megumi Funakoshi-Tago, Masaki Tsukada, Toshiro Watanabe, Yuka Mameda, Kenji Tago, Tomoyuki Ohe, Shigeo Nakamura, Tadahiko Mashino, Tadashi Kasahara

研究成果: Article

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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.

元の言語English
ページ(範囲)258-263
ページ数6
ジャーナルInternational Immunopharmacology
20
発行部数1
DOI
出版物ステータスPublished - 2014 5

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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