Dual blockade of phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer

Rui Xu, Kenji Nakano, Hironori Iwasaki, Michiaki Kumagai, Rie Wakabayashi, Akio Yamasaki, Hiroyuki Suzuki, Ryuichi Mibu, Hideya Ohnishi, Mitsuo Katano

研究成果: ジャーナルへの寄稿記事

17 引用 (Scopus)

抄録

Paclitaxel, one of key drugs to treat a wide range of malignancies, exhibits relative low sensitivity for colorectal cancer. The present study was to examine whether and how phosphatidylinositol 3'-kinase (PI3K) signals affect the sensitivity of colorectal cancer to paclitaxel. Four colorectal cancer cell lines were exposed to paclitaxel in the presence of PI3K signal inhibitors, such as LY294002, siRNA for Akt, or rapamycicn, with or without MAPK inhibitor, PD98059. Cell viability and apoptosis were determined by MTT assay, cell cycle analysis in flow cytometer and Hoechst nuclear staining. To analyze the PI3K activity, the expression in phosphorylated Akt and downstream effectors of p70S6 kinase (S6K) were evaluated by Western blot analysis. Paclitaxel alone (5-10. nM) did not induce the apoptosis in all four cell lines. Although LY294002 alone did not affect the cell viability, it suppressed the Akt and S6K activities and induced the sub-G1 arrest/apoptosis when paclitaxel was co-administered, as well as the Akt siRNA and rapamycin did. Simultaneous blockade of PI3K and MAPK pathways more suppressed the S6K activity and further increased the apoptosis. In conclusion, PI3K is involved in low susceptibility of colorectal cancer to paclitaxel and dual PI3K/MAPK targeting agents may evolve a new paclitaxel-based chemotherapy for colorectal cancer.

元の言語英語
ページ(範囲)151-160
ページ数10
ジャーナルCancer Letters
306
発行部数2
DOI
出版物ステータス出版済み - 7 28 2011

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Phosphatidylinositol 3-Kinase
Paclitaxel
Mitogen-Activated Protein Kinases
Colorectal Neoplasms
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Small Interfering RNA
Cell Survival
Cell Line
Sirolimus
Cell Cycle
Phosphotransferases
Western Blotting
Staining and Labeling
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Dual blockade of phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer. / Xu, Rui; Nakano, Kenji; Iwasaki, Hironori; Kumagai, Michiaki; Wakabayashi, Rie; Yamasaki, Akio; Suzuki, Hiroyuki; Mibu, Ryuichi; Ohnishi, Hideya; Katano, Mitsuo.

:: Cancer Letters, 巻 306, 番号 2, 28.07.2011, p. 151-160.

研究成果: ジャーナルへの寄稿記事

Xu, Rui ; Nakano, Kenji ; Iwasaki, Hironori ; Kumagai, Michiaki ; Wakabayashi, Rie ; Yamasaki, Akio ; Suzuki, Hiroyuki ; Mibu, Ryuichi ; Ohnishi, Hideya ; Katano, Mitsuo. / Dual blockade of phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer. :: Cancer Letters. 2011 ; 巻 306, 番号 2. pp. 151-160.
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abstract = "Paclitaxel, one of key drugs to treat a wide range of malignancies, exhibits relative low sensitivity for colorectal cancer. The present study was to examine whether and how phosphatidylinositol 3'-kinase (PI3K) signals affect the sensitivity of colorectal cancer to paclitaxel. Four colorectal cancer cell lines were exposed to paclitaxel in the presence of PI3K signal inhibitors, such as LY294002, siRNA for Akt, or rapamycicn, with or without MAPK inhibitor, PD98059. Cell viability and apoptosis were determined by MTT assay, cell cycle analysis in flow cytometer and Hoechst nuclear staining. To analyze the PI3K activity, the expression in phosphorylated Akt and downstream effectors of p70S6 kinase (S6K) were evaluated by Western blot analysis. Paclitaxel alone (5-10. nM) did not induce the apoptosis in all four cell lines. Although LY294002 alone did not affect the cell viability, it suppressed the Akt and S6K activities and induced the sub-G1 arrest/apoptosis when paclitaxel was co-administered, as well as the Akt siRNA and rapamycin did. Simultaneous blockade of PI3K and MAPK pathways more suppressed the S6K activity and further increased the apoptosis. In conclusion, PI3K is involved in low susceptibility of colorectal cancer to paclitaxel and dual PI3K/MAPK targeting agents may evolve a new paclitaxel-based chemotherapy for colorectal cancer.",
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AU - Iwasaki, Hironori

AU - Kumagai, Michiaki

AU - Wakabayashi, Rie

AU - Yamasaki, Akio

AU - Suzuki, Hiroyuki

AU - Mibu, Ryuichi

AU - Ohnishi, Hideya

AU - Katano, Mitsuo

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