Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells.
Because the aberrantly activated phosphoinositide 3-kinase (PI3K)/Akt pathway renders tumor cells resistant to cytotoxic insults, including those related to anticancer drugs, inhibition of the pathway may possibly restore or augment the effectiveness of chemotherapy. Using the human malignant glioma cell lines U87, A172, LN18, and LN229, we examined effects of the PI3K inhibitor LY294002 on both apoptosis and cytotoxicity induced by chemotherapeutic agents, including antimicrotubule agents vincristine and paclitaxel, an alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea, a topoisomerase II inhibitor etoposide, and a DNA cross-linking agent cisplatin (cis-diamminedichloroplatinum), and we compared the LY294002-induced enhancement of effects of those agents. Ten to 20 micro M LY294002 augmented both apoptosis and caspase 3-like activity caused by antimicrotubule agents to a larger extent than induced by 1,3-bis(2-chloroethyl)-1-nitrosourea, etoposide, and cisplatin in all four malignant glioma cell lines examined. The same doses of LY294002 enhanced cytotoxicity more efficiently with antimicrotubule agents than with other chemotherapeutic agents. Quantitative analyses using a modified isobologram and median effect plot method revealed that enhancement by LY294002 of vincristine- or paclitaxel-induced cytotoxicity was synergistic, whereas enhancement by the PI3K inhibitor of the other chemotherapeutic agent-induced cytotoxicity was additive. Our study indicates that the synergistic augmentation of the cytotoxicity by LY294002 occurs specifically with antimicrotubule agents, at least partially through an increase in caspase 3-dependent apoptosis, and we suggest that inhibitors of the PI3K/Akt pathway in combination with antimicrotubule agents may induce cell death effectively and be a potent modality to treat patients with malignant gliomas.
Shingu
Takashi
T
Department of Biochemistry, Shimane Medical University, Izumo 693-8501, Japan. nogeka@shimane-med.ac.jp
Yamada
Kazuo
K
Hara
Nobumasa
N
Moritake
Kouzo
K
Osago
Harumi
H
Terashima
Masaharu
M
Uemura
Takeshi
T
Yamasaki
Toshiki
T
Tsuchiya
Mikako
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002330:Carmustine / Q000008:administration & dosage / Q000494:pharmacology; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000008:administration & dosage / Q000494:pharmacology
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D014750:Vincristine; D005047:Etoposide; D017239:Paclitaxel; D002945:Cisplatin; D002330:Carmustine