Evaluation of GL331 in combination with paclitaxel: GL331's interference with paclitaxel-induced cell cycle perturbation and apoptosis.

Abstract	Combination of selecting agents that act on different cellular mechanisms is a common strategy in cancer chemotherapy. GL331 is a new potent topoisomerase II (Topo II) poison; distinctly, paclitaxel is a microtubule-interfering cancer chemotherapeutic agent. In this study, we intended to evaluate the efficacy of combining GL331 with paclitaxel in cell killing and apoptotic induction in nasopharyngeal carcinoma NPC-TW01 cells. By MTT and internucleosomal DNA cleavage assays, we found that pretreatment or simultaneous treatment of NPC-TW01 cells with GL331 could significantly interfere with paclitaxel's cell killing and apoptosis-inducing activity. When the administration schedule was reversed, the cytotoxicity of GL331 was attenuated by paclitaxel pretreatment. The anti-cancer activity produced by combining GL331 with paclitaxel was obviously lower than the addition of the activities of two individual agents. NPC-TW01 cells were treated with GL331 and 3H-labeled paclitaxel simultaneously or with GL331 before 3H-labeled paclitaxel. In both conditions, GL331 did not reduce the [3H]paclitaxel level in the cells, suggesting that GL331's interference with paclitaxel's cell-killing and apoptosis-inducing efficacy did not result from any inhibition of cellular uptake or retention of paclitaxel. In addition, we found that GL331-induced perturbation of cell cycle progression dramatically over-rode the patterns of mitotic arrest induced by paclitaxel, and the mechanism could be the inhibition of cyclin B1/CDC2 kinase and MAD2 checkprotein activities.
Authors	T S Huang, C H Shu, Y Chao, L T Chen
Journal	Anti-cancer drugs (Anticancer Drugs) Vol. 12 Issue 3 Pg. 259-66 (Mar 2001) ISSN: 0959-4973 [Print] England
PMID	11290873 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents, Phytogenic CCNB1 protein, human Calcium-Binding Proteins Carrier Proteins Cell Cycle Proteins Cyclin B Cyclin B1 DNA, Neoplasm Fungal Proteins Nuclear Proteins Tetrazolium Salts Thiazoles GL 331 Etoposide Protein Kinases histone H1 kinase CDC2 Protein Kinase thiazolyl blue Paclitaxel
Topics	Antineoplastic Agents, Phytogenic (administration & dosage) Antineoplastic Combined Chemotherapy Protocols (pharmacology) Apoptosis (drug effects) Blotting, Western CDC2 Protein Kinase (drug effects, metabolism) Calcium-Binding Proteins (drug effects, metabolism) Carrier Proteins Cell Cycle (drug effects) Cell Cycle Proteins Cell Nucleus (drug effects) Cyclin B (drug effects, metabolism) Cyclin B1 DNA, Neoplasm (analysis) Dose-Response Relationship, Drug Drug Antagonism Drug Evaluation Drug Interactions Drug Therapy, Combination Etoposide (administration & dosage, analogs & derivatives) Flow Cytometry Fungal Proteins (drug effects, metabolism) Humans Nasopharyngeal Neoplasms (drug therapy, metabolism) Nuclear Proteins Paclitaxel (administration & dosage) Precipitin Tests Protein Kinases (metabolism) Tetrazolium Salts Thiazoles Toxicity Tests Tumor Cells, Cultured (drug effects, metabolism)

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