Promotion of in vivo 5-aminolevulinic acid-photodynamic therapy efficacy by MEK inhibition

Som, Jayoti (2020) Promotion of in vivo 5-aminolevulinic acid-photodynamic therapy efficacy by MEK inhibition. Masters thesis, Memorial University of Newfoundland.

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Abstract

Protoporphyrin IX (PpIX), a heme precursor, is a photosensitizer that is selectively accumulated in cancer cells when pretreated with its precursor, 5-aminolevulinic acid (5-ALA). Exposure of PpIX accumulating-cancer cells to red light induces the generation of reactive oxygen species (ROS) and subsequent stimulation of cancer cell death, which is known as 5-ALA-photodynamic therapy (5-ALA-PDT). Previously, Dr. Hirasawa's lab discovered that inhibiting the oncogenic Ras/MEK pathway increases PpIX accumulation in cancer cells by suppressing PpIX efflux and PpIX conversion to heme. Here, we sought to determine whether the increase of PpIX accumulation by MEK inhibition promotes 5-ALA-PDT efficacy. First, we classified seven human cancer cell lines into three groups – sensitive, moderately sensitive, and least sensitive –based on their sensitivities to 5-ALA-PDT. Pretreating the moderately sensitive and least sensitive cell lines with a MEK inhibitor increased their sensitivities to 5-ALA-PDT, suggesting that MEK activity influences PDT sensitivity of cancer cells. MEK inhibition promoted 5-ALA-PDT induced generation of ROS and the subsequent programmed cell death. Furthermore, combined 5-ALA-PDT with a MEK inhibitor was significantly effective in inhibiting the growth of tumors in nude mice implanted with human colon cancer cells (DLD-1) and increased their overall survival. As the efficacy and safety of MEK inhibitors are clinically established, combined 5-ALA-PDT with MEK inhibition could directly impact 5-ALA-PDT applications in the clinic.

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