title: High antitumor activity of pladienolide B and its derivative in gastric cancer.
abstract: The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6-4.0) and 1.2 ± 1.1 (range, 0.4-3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.
authors.affiliation: Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Sato
authors.forename: Naoki
authors.initials: N
authors.lastname: Muguruma
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kimura
authors.forename: Shinji
authors.initials: S
authors.lastname: Kitamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yano
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Sannomiya
authors.forename: Takahiro
authors.initials: T
authors.lastname: Goji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okahisa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mikasa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Wada
authors.forename: Masao
authors.initials: M
authors.lastname: Iwata
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Takayama
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004852:Epoxy Compounds / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D018942:Macrolides / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D011897:Random Allocation; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004852:Epoxy Compounds; D018942:Macrolides; C522342:pladienolide B
keywords: Apoptosis; RNA splicing; ascites; gastric cancer; pladienolide B