Evaluation of GL331 in combination with paclitaxel: GL331's interference with paclitaxel-induced cell cycle perturbation and apoptosis.
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.
Huang
T S
TS
Cooperative Laboratory, Cancer Research Division, National Health Research Institutes; Taipei, Taiwan, ROC. tshuang@nhri.org.tw
Shu
C H
CH
Chao
Y
Y
Chen
L T
LT
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000187:drug effects; D019926:Cyclin B / Q000187:drug effects / Q000378:metabolism; D056744:Cyclin B1; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004341:Drug Evaluation; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005047:Etoposide / Q000008:administration & dosage / Q000031:analogs & derivatives; D005434:Flow Cytometry; D005656:Fungal Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009687:Nuclear Proteins; D017239:Paclitaxel / Q000008:administration & dosage; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D004273:DNA, Neoplasm; D005656:Fungal Proteins; D009687:Nuclear Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; C121391:GL 331; D005047:Etoposide; D011494:Protein Kinases; C102333:histone H1 kinase; D016203:CDC2 Protein Kinase; C022616:thiazolyl blue; D017239:Paclitaxel