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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2003-07, Vol.63 (14), p.4044-4047
Main Authors: SHINGU, Takashi, YAMADA, Kazuo, HARA, Nobumasa, MORITAKE, Kouzo, OSAGO, Harumi, TERASHIMA, Masaharu, UEMURA, Takeshi, YAMASAKI, Toshiki, TSUCHIYA, Mikako
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Carmustine - administration & dosage
Carmustine - pharmacology
Chemotherapy
Chromones - administration & dosage
Chromones - pharmacology
Cisplatin - administration & dosage
Cisplatin - pharmacology
Drug Synergism
Enzyme Inhibitors - administration & dosage
Enzyme Inhibitors - pharmacology
Etoposide - administration & dosage
Etoposide - pharmacology
Glioma - drug therapy
Glioma - enzymology
Humans
Medical sciences
Microtubules - drug effects
Morpholines - administration & dosage
Morpholines - pharmacology
Paclitaxel - administration & dosage
Paclitaxel - pharmacology
Pharmacology. Drug treatments
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Tumor Cells, Cultured
Vincristine - administration & dosage
Vincristine - pharmacology
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Summary: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.
ISSN:0008-5472
1538-7445