title: Effect of chemical modification on the ability of pyrrolidinium fullerene to induce apoptosis of cells transformed by JAK2 V617F mutant.
abstract: 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.
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Electronic address: tago-mg@pha.keio.ac.jp.
authors.forename: Megumi
authors.initials: M
authors.lastname: Funakoshi-Tago
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tsukada
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mameda
authors.affiliation: Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken 329-0498, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tago
authors.affiliation: Department of Medicinal Chemistry and Bio-organic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.affiliation: Department of Chemistry, Nippon Medical School, 2-297-2 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-0063, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Medicinal Chemistry and Bio-organic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kasahara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D037741:Fullerenes / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000235:genetics*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009154:Mutation; D011759:Pyrrolidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D037741:Fullerenes; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: ASK1; JAK2; JNK; Myeloproliferative neoplasms; Pyrrolidinium fullerene; V617F mutation