title: Dual blockade of phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer.
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 rapamycin, 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.
authors.affiliation: Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Japan.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakano
authors.forename: Hironori
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kumagai
authors.forename: Rie
authors.initials: R
authors.lastname: Wakabayashi
authors.forename: Akio
authors.initials: A
authors.lastname: Yamasaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Mibu
authors.forename: Hideya
authors.initials: H
authors.lastname: Onishi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Katano
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one