High antitumor activity of pladienolide B and its derivative in gastric cancer.
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| 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.
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| Authors | Momoko Sato, Naoki Muguruma, Tadahiko Nakagawa, Koichi Okamoto, Tetsuo Kimura, Shinji Kitamura, Hiromi Yano, Katsutaka Sannomiya, Takahiro Goji, Hiroshi Miyamoto, Toshiya Okahisa, Hiroaki Mikasa, Satoshi Wada, Masao Iwata, Tetsuji Takayama |
| Journal | Cancer science (Cancer Sci) Vol. 105 Issue 1 Pg. 110-6 (Jan 2014) ISSN: 1349-7006 [Electronic] England |
| PMID | 24635824 (Publication Type: Journal Article) |
| Copyright | © 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. |
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