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High antitumor activity of pladienolide B and its derivative in gastric cancer.

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 - Cancer Sci. (2013)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.

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Related in: MedlinePlus

Splicing inhibition and apoptosis induction in gastric cancer cells in vitro and in vivo by the pladienolide B derivative. (a) MKN74 cells were treated with pladienolide B derivative for 4 h and unspliced mRNA of RIOK3 and DNAJB1 genes were evaluated using RT-PCR. G, Genomic DNA as a control; S, spliced mRNA; U, unspliced mRNA. (b) MKN74 cells were treated with the pladienolide B derivative and apoptotic cells were detected using TUNEL staining. (c) Mice with xenografts from MKN74 cells were treated with pladienolide B derivative (10 mg/kg) or vehicle four times and unspliced mRNA of excised xenografts were evaluated using RT-PCR. (d) Apoptotic cells in the xenograft tumors were detected using TUNEL staining. *P < 0.01.
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fig03: Splicing inhibition and apoptosis induction in gastric cancer cells in vitro and in vivo by the pladienolide B derivative. (a) MKN74 cells were treated with pladienolide B derivative for 4 h and unspliced mRNA of RIOK3 and DNAJB1 genes were evaluated using RT-PCR. G, Genomic DNA as a control; S, spliced mRNA; U, unspliced mRNA. (b) MKN74 cells were treated with the pladienolide B derivative and apoptotic cells were detected using TUNEL staining. (c) Mice with xenografts from MKN74 cells were treated with pladienolide B derivative (10 mg/kg) or vehicle four times and unspliced mRNA of excised xenografts were evaluated using RT-PCR. (d) Apoptotic cells in the xenograft tumors were detected using TUNEL staining. *P < 0.01.

Mentions: To determine whether the pladienolide B derivative inhibits splicing of pre-mRNA in gastric cancer cells, we first treated MKN74 cells in vitro with various doses of the drug and evaluated the amount of unspliced mRNA of the RIOK3 or DNAJB1 genes, as described previously.9,13 In untreated cells, only mature mRNA (spliced mRNA) were identified and unspliced mRNA was not observed or was observed very faintly. However, in the treatment group, unspliced mRNA of RIOK3 and DNAJB1 genes were clearly observed and the amounts of unspliced mRNA increased in a dose-dependent manner (Fig. 3a).


High antitumor activity of pladienolide B and its derivative in gastric cancer.

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 - Cancer Sci. (2013)

Splicing inhibition and apoptosis induction in gastric cancer cells in vitro and in vivo by the pladienolide B derivative. (a) MKN74 cells were treated with pladienolide B derivative for 4 h and unspliced mRNA of RIOK3 and DNAJB1 genes were evaluated using RT-PCR. G, Genomic DNA as a control; S, spliced mRNA; U, unspliced mRNA. (b) MKN74 cells were treated with the pladienolide B derivative and apoptotic cells were detected using TUNEL staining. (c) Mice with xenografts from MKN74 cells were treated with pladienolide B derivative (10 mg/kg) or vehicle four times and unspliced mRNA of excised xenografts were evaluated using RT-PCR. (d) Apoptotic cells in the xenograft tumors were detected using TUNEL staining. *P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4317874&req=5

fig03: Splicing inhibition and apoptosis induction in gastric cancer cells in vitro and in vivo by the pladienolide B derivative. (a) MKN74 cells were treated with pladienolide B derivative for 4 h and unspliced mRNA of RIOK3 and DNAJB1 genes were evaluated using RT-PCR. G, Genomic DNA as a control; S, spliced mRNA; U, unspliced mRNA. (b) MKN74 cells were treated with the pladienolide B derivative and apoptotic cells were detected using TUNEL staining. (c) Mice with xenografts from MKN74 cells were treated with pladienolide B derivative (10 mg/kg) or vehicle four times and unspliced mRNA of excised xenografts were evaluated using RT-PCR. (d) Apoptotic cells in the xenograft tumors were detected using TUNEL staining. *P < 0.01.
Mentions: To determine whether the pladienolide B derivative inhibits splicing of pre-mRNA in gastric cancer cells, we first treated MKN74 cells in vitro with various doses of the drug and evaluated the amount of unspliced mRNA of the RIOK3 or DNAJB1 genes, as described previously.9,13 In untreated cells, only mature mRNA (spliced mRNA) were identified and unspliced mRNA was not observed or was observed very faintly. However, in the treatment group, unspliced mRNA of RIOK3 and DNAJB1 genes were clearly observed and the amounts of unspliced mRNA increased in a dose-dependent manner (Fig. 3a).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Oncology, Institutes of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan.

Show MeSH
Related in: MedlinePlus