Promotion of protoporphyrin IX (PpIX) fluorescence by MEK inhibition in animal models of cancer
Year: 2016
Type: dissertation
Abstract: Background: Protoporphyrin IX (PpIX) is an endogenous fluorescence that is \naccumulated in cancer cells treated with the heme precursor 5-aminolevulinic \nacid (5-ALA). The cancer-specific fluorescence of PpIX is used to distinguish \ntumor from normal tissue, which has proven clinically useful during fluorescence-image \nguided surgery. This study sought to investigate whether modulation of \noncogenic Ras/MEK pathway mediates PpIX accumulation in vitro and in vivo. \nMethods: For in vitro studies, human breast, lung and prostate cancer cells were \ntreated with or without the MEK inhibitor (U0126) for 20 hours, followed with 5- \nALA for 5 hours. The cells were lysed, and the PpIX fluorescence accumulated in \nthe cells was measured with a microplate fluorescence reader (λex 405 nm; \nλem635 nm). For in vivo studies, the 4T1 mouse breast cancer cells were \ninjected into the right hind flank of 8 week-old Balb/c female mice. U0126 (50 \nμM/Kg) was injected intratumourally to 4T1 breast tumors for 5/8 h followed by 5- \nALA injection. Mice bearing 4T1 breast tumors were also injected \nintraperitoneally with U0126 for 5 or 8. Furthermore, similar experiments were \nconducted using a HRAS transgenic mice, which develop spontaneous \nmammary tumors within 3 months old. Results: In vitro, MEK inhibition increases \nPpIX fluorescence in human cancer cell lines, but not in normal cell lines. The \npromotion of PpIX fluorescence by MEK inhibition was most commonly observed \namong human breast cancer cells. In vivo, PpIX accumulation was observed \nsignificantly more in the tumors from mice treated with U0126 and 5-ALA (2-3 \nfold) than those from mice with vehicle control (DMSO/saline) and 5-ALA. \nConclusions: In vitro and in vivo treatment of the MEK inhibitor significantly \nincreases the accumulation of PpIX fluorescence in cancer cells which may \ncontribute to improved efficacy of FGS in clinical settings.
Author: Ema Yoshioka
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2944049511