Enhanced cell growth inhibition by thiacremonone in paclitaxel-treated lung cancer cells.

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.

• Authors: Jung Ok Ban, Chul Ju Hwang, Mi Hee Park, In-Kook Hwang, Heon-Sang Jeong, Hee Pom Lee, Byoung Kook Hyun, Ji Young Kim, Hae Suk Youn, Young Wan Ham, Do Young Yoon, Sang-Bae Han, Min Jong Song, Jin Tae Hong
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 38 Issue 7 Pg. 1351-62 (Jul 2015) ISSN: 1976-3786 [Electronic] Korea (South)
• PMID: 25791937 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Growth Inhibitors
• NF-kappa B
• NF-kappa B p50 Subunit
• Thiophenes
• thiacremonone
• Poly(ADP-ribose) Polymerases
• Caspase 8
• Paclitaxel

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 8 (biosynthesis)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Growth Inhibitors (pharmacology)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• NF-kappa B (antagonists & inhibitors)
• NF-kappa B p50 Subunit (metabolism)
• Neoplastic Stem Cells (drug effects)
• Paclitaxel (pharmacology)
• Poly(ADP-ribose) Polymerases (biosynthesis)
• Thiophenes (pharmacology)