High antitumor activity of pladienolide B and its derivative in gastric cancer.
Bottom Line: 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.
Affiliation: Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.Show MeSH
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Mentions: We previously found preliminary data showing a positive correlation between pladienolide B derivative sensitivity and expression of p16 or cyclin E in lung cancer and breast cancer cell lines.22 Therefore, in the present study, we examined p16 and cyclin E expression in biopsied human gastric cancer tissue using immunohistochemical staining. Figure 4(A) shows three representative strong positive (panels a,d), weak positive (panels b,e) and negative (panels c,f) staining patterns for p16. In Figure 4(A-D), the nuclei of the majority of cancer cells (>75%) were stained dark brown and were categorized as strong positive according to the evaluation scheme described in the Materials and Methods. In Figure 4(A-E), the nuclei of 25–50% of cancer cells were stained brown (weak positive). In Figure 4(A-F), <25% of cells were stained light brown (negative). Out of a total of 12 cases, three cases were strong positive, three cases were weak positive and six cases were negative. When the primary cultured cells were classified according to whether the IC50 was equal to or greater than the median value of 3.25 nM (high IC50 group) or lower than 3.25 nM (low IC50 group), p16 positivity in the low IC50 group was significantly higher than in the high IC50 group (P = 0.047; Fig. 4C). These results indicate that cancer cells with high expression of p16 had a low IC50 and were more sensitive to the pladienolide B derivative.
Affiliation: Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.