| 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 |
2014-1-1
|
| 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 |
4.966
|
| Times Cited |
23
|
|
WOS Category
|
ONCOLOGY
|
| Resource |
| Human and Animal Cells |
HGC-27(RCB0500)
NUGC-4(RCB1939)
Lu99(RCB1900)
T3M-11(RCB1022)
MDA-MB-453(RCB1192) |
