التفاصيل البيبلوغرافية
| العنوان: |
Systemic MEK inhibition enhances the efficacy of 5-aminolevulinic acid-photodynamic therapy. |
| المؤلفون: |
Chelakkot, Vipin Shankar1 (AUTHOR), Som, Jayoti1 (AUTHOR), Yoshioka, Ema1 (AUTHOR), Rice, Chantel P.1 (AUTHOR), Rutihinda, Suzette G.1 (AUTHOR), Hirasawa, Kensuke1 (AUTHOR) kensuke@mun.ca |
| المصدر: |
British Journal of Cancer. Oct2019, Vol. 121 Issue 9, p758-767. 10p. 1 Diagram, 5 Graphs. |
| مستخلص: |
Background: Protoporphyrin IX (PpIX) gets accumulated preferentially in 5-aminolevulinic acid (5-ALA)-treated cancer cells. Photodynamic therapy (PDT) utilises the accumulated PpIX to trigger cell death by light-induced generation of reactive oxygen species (ROS). We previously demonstrated that oncogenic Ras/MEK decreases PpIX accumulation in cancer cells. Here, we investigated whether combined therapy with a MEK inhibitor would improve 5-ALA-PDT efficacy.Methods: Cancer cells and mice models of cancer were treated with 5-ALA-PDT, MEK inhibitor or both MEK inhibitor and 5-ALA-PDT, and treatment efficacies were evaluated.Results: Ras/MEK negatively regulates the cellular sensitivity to 5-ALA-PDT as cancer cells pre-treated with a MEK inhibitor were killed more efficiently by 5-ALA-PDT. MEK inhibition promoted 5-ALA-PDT-induced ROS generation and programmed cell death. Furthermore, the combination of 5-ALA-PDT and a systemic MEK inhibitor significantly suppressed tumour growth compared with either monotherapy in mouse models of cancer. Remarkably, 44% of mice bearing human colon tumours showed a complete response with the combined treatment.Conclusion: We demonstrate a novel strategy to promote 5-ALA-PDT efficacy by targeting a cell signalling pathway regulating its sensitivity. This preclinical study provides a strong basis for utilising MEK inhibitors, which are approved for treating cancers, to enhance 5-ALA-PDT efficacy in the clinic. [ABSTRACT FROM AUTHOR] |
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