Abstract
5-Aminolevulinic acid (ALA), a precursor of porphyrin, is specifically converted to the fluorescent substance protoporphyrin IX (PpIX) in tumors to be used as a prodrug for photodynamic therapy and diagnosis. Hypoxia, a common feature of solid tumors, decreases the efficacy of ALA-based photodynamic therapy and diagnosis. This decrease results from the excretion of porphyrin precursor coproporphyrinogen III (CPgenIII), an intermediate in the biosynthesis of PpIX. However, the mechanism of CPgenIII excretion during hypoxia remains unclear. In this study, we revealed the importance of mitochondrial respiration for the production of PpIX during hypoxia. Porphyrin concentrations were estimated in human gastric cancer cell lines by HPLC. Expression levels of porphyrin biosynthesis genes were measured by qRT-PCR and immunoblotting. Blockage of porphyrin biosynthesis was an oxygen-dependent phenomenon resulting from decreased PpIX production in mitochondria under hypoxic conditions. PpIX production was increased by the inhibition of mitochondrial respiration complexes, which indicates that the enzymes of porphyrin biosynthesis compete with respiration complexes for molecular oxygen. Our results indicate that targeting the respiration complexes is a rationale for enhancing the effect of ALA-mediated treatment and diagnosis.
Highlights
Hypoxia, a pathologic microenvironment that occurs in solid tumors, is caused by their incomplete vascular structure and limited perfusion [4]
Our previous studies have shown that protoporphyrin IX (PpIX) synthesis is decreased and coproporphyrin III (CPIII) excretion is increased during hypoxia [15]
To examine the details of this alteration of porphyrin biosynthesis during hypoxia, we examined the accumulation of PpIX and CPIII after altering the oxygen concentration
Summary
5-Aminolevulinic acid (ALA) is a precursor in the porphyrin biosynthetic pathway, which produces the bioactive molecule heme. When ALA is administered to cancer patients, cancer cells accumulate the fluorescence precursor protoporphyrin IX (PpIX), PpIX is converted to heme in normal cells. The activity of ALA hydrogenase and the expression level of ferrochelatase (FECH), the second and eighth enzymes of porphyrin-heme biosynthesis pathway, respectively, are increased in hypoxia, resulting in an increase in heme biosynthesis [10,11,12]. The expression level of the human ABC transporter ABCG2, previously identified as a PpIX export transporter, is increased in hypoxia [14]. It is unclear whether these changes in expression level affect the ALA-mediated accumulation of PpIX in hypoxia. These results indicate that targeting mitochondrial respiration is expected to enhance the effect of ALA-PDT in clinical situations
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