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MEK inhibition enhances paclitaxel-induced tumor apoptosis
J P MacKeigan1, T S Collins, J P Ting
1Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Abstract:
The anti-cancer drug paclitaxel (Taxol) alters microtubule assembly and activates pro-apoptotic signaling pathways. Previously, we and others found that paclitaxel activates endogenous JNK in tumor cells, and the activation of JNK contributes to tumor cell apoptosis. Here we find that paclitaxel activates the prosurvival MEK/ERK pathway, which conversely may compromise the efficacy of paclitaxel. Hence, a combination treatment of paclitaxel and MEK inhibitors was pursued to determine whether this treatment could lead to enhanced apoptosis. The inhibition of MEK/ERK with a pharmacologic inhibitor, U0126, together with paclitaxel resulted in a dramatic enhancement of apoptosis that is four times more than the additive value of the two drugs alone. Enhanced apoptosis was verified by the terminal transferase-mediated dUTP nick end labeling assay, by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and by flow cytometric analysis for DNA content. Specificity of the pharmacologic inhibitor was confirmed by the use of (a) a second MEK/ERK inhibitor and (b) a transdominant-negative MEK. Enhanced apoptosis was verified in breast, ovarian, and lung tumor cell lines, suggesting this effect is not cell type-specific. This is the first report of enhanced apoptosis detected in the presence of paclitaxel and MEK inhibition and suggests a new anticancer strategy.
Insights
Combining paclitaxel with MEK inhibitors significantly enhances cancer cell apoptosis. This novel strategy, targeting both JNK and MEK/ERK pathways, shows promise for improved anti-cancer efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Paclitaxel (Taxol) is an anti-cancer drug that induces apoptosis by affecting microtubule assembly.
- Paclitaxel activates the JNK pathway, contributing to tumor cell death.
- Paclitaxel also activates the prosurvival MEK/ERK pathway, potentially limiting its efficacy.
Purpose of the Study:
- To investigate the combined effect of paclitaxel and MEK inhibitors on cancer cell apoptosis.
- To determine if inhibiting the MEK/ERK pathway can enhance paclitaxel-induced apoptosis.
Main Methods:
- Utilized a pharmacologic MEK inhibitor (U0126) in combination with paclitaxel.
- Verified enhanced apoptosis using TUNEL assay, ELISA for DNA fragments, and flow cytometry.
- Confirmed inhibitor specificity with a second MEK inhibitor and transdominant-negative MEK.
Main Results:
- Combination treatment with paclitaxel and U0126 dramatically enhanced apoptosis, exceeding additive effects.
- Enhanced apoptosis was observed in breast, ovarian, and lung tumor cell lines.
- The combination therapy demonstrated a synergistic effect on cancer cell death.
Conclusions:
- Inhibiting the MEK/ERK pathway in conjunction with paclitaxel significantly boosts apoptosis.
- This combination strategy offers a promising new approach for cancer treatment.
- The findings suggest a potential for enhanced therapeutic outcomes in various cancer types.