RRC ID 44971
Author Sato M, Muguruma N, Nakagawa T, Okamoto K, Kimura T, Kitamura S, Yano H, Sannomiya K, Goji T, Miyamoto H, Okahisa T, Mikasa H, Wada S, Iwata M, Takayama T.
Title High antitumor activity of pladienolide B and its derivative in gastric cancer.
Journal Cancer Sci.
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.
Volume 105(1)
Pages 110-6
Published 2014-1
DOI 10.1111/cas.12317
PMID 24635824
PMC PMC4317874
MeSH Aged Aged, 80 and over Animals Antineoplastic Agents / therapeutic use* Apoptosis / drug effects Apoptosis / genetics Cell Line, Tumor Cyclin E / genetics Cyclin-Dependent Kinase Inhibitor p16 / genetics Epoxy Compounds / therapeutic use* Female Humans Macrolides / therapeutic use* Male Mice Mice, SCID Middle Aged RNA Splicing / drug effects RNA Splicing / genetics Random Allocation Stomach Neoplasms / drug therapy* Stomach Neoplasms / genetics Xenograft Model Antitumor Assays
IF 4.372
Times Cited 11
Human and Animal Cells