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Long-term Live-cell Imaging to Assess Cell Fate in Response to Paclitaxel
Published on: May 14, 2018
Enhanced cell growth inhibition by thiacremonone in paclitaxel-treated lung cancer cells
Jung Ok Ban1, Chul Ju Hwang, Mi Hee Park
1College of Pharmacy and Medical Research Center, Chungbuk National University, 52, Naesudong-ro, Heungdeok-gu, Cheongju, Chungbuk, 361-763, Republic of Korea.
Abstract:
Activation of nuclear factor kappa-B (NF-κB) is implicated in drug resistant of lung cancer cells. Our previous data showed that thiacremonone inhibited activation of NF-κB. In the present study, we investigated whether thiacremonone enhanced susceptibility of lung cancer cells to a common anti-cancer drug paclitaxel by further inhibition of NF-κB. Thus, we used the threefold lower doses of IC50 values (50 μg/ml thiacremonone and 2.5 nM paclitaxel). We found that combination treatment with thiacremonone and paclitaxel was more susceptible (combination index; 0.40 in NCI-H460 cells and 0.46 in A549 cells) in cell growth inhibition of two types of lung cancer cell lines compared to a single agent treatment. Consistent with the combination effect on cancer cell growth inhibition, the combination treatment further induced apoptotic cell death and arrested the cancer cells in G2/M phase accompanied with a much lower expression of cdc2 and cyclin B1, and inhibited colony formation. Much more inactivation of NF-κB and greater expression of NF-κB target apoptosis regulated genes such as caspase-8 and PARPs were found by the combination treatment. Molecular model and pull down assay as well as MALDI-TOF analysis demonstrated that thiacremonone directly binds to p50. These data indicated that thiacremonone leads to increased apoptotic cell death in lung cancer cell lines through greater inhibition of NF-κB by the combination treatment with paclitaxel.
Insights
Thiacremonone enhances lung cancer cell susceptibility to paclitaxel by further inhibiting nuclear factor kappa-B (NF-κB). This combination therapy promotes apoptosis and cell cycle arrest, offering a promising strategy for drug-resistant lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Nuclear factor kappa-B (NF-κB) activation is linked to drug resistance in lung cancer.
- Previous studies indicated thiacremonone inhibits NF-κB activation.
Purpose of the Study:
- To investigate if thiacremonone enhances lung cancer cell susceptibility to paclitaxel by further inhibiting NF-κB.
- To evaluate the combined effects of thiacremonone and paclitaxel on lung cancer cell lines.
Main Methods:
- Combination treatment using sub-IC50 doses of thiacremonone (50 μg/ml) and paclitaxel (2.5 nM).
- Assessed cell growth inhibition, apoptosis, cell cycle arrest (G2/M phase), colony formation, and NF-κB activity.
- Analyzed expression of apoptosis-related genes (caspase-8, PARPs) and cell cycle regulators (cdc2, cyclin B1).
- Utilized molecular modeling, pull-down assays, and MALDI-TOF to determine thiacremonone's binding target.
Main Results:
- Combination therapy showed synergistic effects (combination index < 1) in inhibiting cell growth in NCI-H460 and A549 cell lines.
- The combined treatment significantly induced apoptosis and G2/M cell cycle arrest, with reduced cdc2 and cyclin B1 expression.
- Greater inactivation of NF-κB and increased expression of NF-κB target genes (caspase-8, PARPs) were observed with combination therapy.
- Thiacremonone was found to directly bind to the p50 subunit of NF-κB.
Conclusions:
- Thiacremonone potentiates paclitaxel's anti-cancer effects in lung cancer cells.
- The combination therapy enhances apoptosis and overcomes drug resistance through combined NF-κB inhibition.
- Thiacremonone's direct binding to p50 is a key mechanism for its synergistic effect with paclitaxel.
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