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Evaluation of GL331 in combination with paclitaxel: GL331's interference with paclitaxel-induced cell cycle
1Cooperative Laboratory, Cancer Research Division, National Health Research Institutes; Taipei, Taiwan, ROC. tshuang@nhri.org.tw
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.
Insights
Combining GL331, a topoisomerase II poison, with paclitaxel, a microtubule agent, reduces nasopharyngeal carcinoma cell killing and apoptosis. GL331 interferes with paclitaxel
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Combination chemotherapy utilizes agents targeting diverse cellular mechanisms.
- GL331 is a novel topoisomerase II (Topo II) poison.
- Paclitaxel is a microtubule-interfering chemotherapeutic agent.
Purpose of the Study:
- To evaluate the combined efficacy of GL331 and paclitaxel in nasopharyngeal carcinoma (NPC) cells.
- To assess the impact of administration sequence on combined anti-cancer activity.
- To elucidate the mechanisms underlying the interaction between GL331 and paclitaxel.
Main Methods:
- MTT assays for cell viability.
- Internucleosomal DNA cleavage assays for apoptosis.
- Radioactive tracer studies ([3H]-paclitaxel) for drug uptake and retention.
- Cell cycle progression analysis.
Main Results:
- GL331 pretreatment or co-treatment significantly inhibited paclitaxel's cell-killing and apoptosis-inducing effects in NPC-TW01 cells.
- Paclitaxel pretreatment attenuated GL331's cytotoxicity.
- Combined anti-cancer activity was less than additive.
- GL331 did not affect paclitaxel cellular uptake or retention.
- GL331-induced cell cycle perturbation overrode paclitaxel-induced mitotic arrest, potentially via inhibition of cyclin B1/CDC2 kinase and MAD2 activity.
Conclusions:
- The combination of GL331 and paclitaxel demonstrates antagonistic effects in NPC cells, reducing overall anti-cancer efficacy.
- GL331's interference mechanism involves overriding paclitaxel-induced mitotic arrest through cell cycle regulation, not altered drug uptake.
- Optimizing administration schedules is crucial for combination cancer chemotherapy.