title: PKC/MEK inhibitors suppress oxaliplatin-induced neuropathy and potentiate the antitumor effects.
abstract: Oxaliplatin is a key drug commonly used in colorectal cancer treatment. Despite high clinical efficacy, its therapeutic application is limited by common, dose-limiting occurrence of neuropathy. As usual symptomatic neuropathy treatments fail to improve the patients' condition, there is an urgent need to advance our understanding of the pathogenesis of neuropathy to propose effective therapy and ensure adequate pain management. Oxaliplatin-induced neuropathy was recently reported to be associated with protein kinase C (PKC) activation. It is unclear, however, whether PKC inhibition can prevent neuropathy. In our current studies, we found that a PKC inhibitor, tamoxifen, inhibited oxaliplatin-induced neuropathy via the PKC/extracellular signal-regulated kinase (ERK)/c-Fos pathway in lumbar spinal cords (lumbar segments 4-6). Additionally, tamoxifen was shown to act in synergy with oxaliplatin to inhibit growth in tumor cells-implanted mice. Moreover, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, PD0325901, suppressed oxaliplatin-induced neuropathy and enhanced oxaliplatin efficacy. Our results indicate that oxaliplatin-induced neuropathy is associated with PKC/ERK/c-Fos pathway in lumbar spinal cord. Additionally, we demonstrate that disruption of this pathway by PKC and MEK inhibitors suppresses oxaliplatin-induced neuropathy, thereby suggesting that PKC and MEK inhibitors may be therapeutically useful in preventing oxaliplatin-induced neuropathy and could aid in combination antitumor pharmacotherapy.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.forename: Tomoya
authors.initials: T
authors.lastname: Takeda
authors.forename: Tadahumi
authors.initials: T
authors.lastname: Tani
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shimaoka
authors.forename: Naohiro
authors.initials: N
authors.lastname: Suzuyama
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Arisa
authors.initials: A
authors.lastname: Fujita
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogawa
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Funakami
authors.forename: Seiji
authors.initials: S
authors.lastname: Ichida
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000077150:Oxaliplatin; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D001549:Benzamides; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D000077150:Oxaliplatin; D013629:Tamoxifen; C506614:mirdametinib; D004159:Diphenylamine
keywords: MEK; PKC; neuropathy; oxaliplatin