Abstract
Aminolevulinic acid (ALA) is the first metabolite in the heme biosynthesis pathway in humans. In addition to the end product heme, this pathway also produces other porphyrin metabolites. Protoporphyrin (PpIX) is one heme precursor porphyrin with good fluorescence and photosensitizing activity. Because tumors and other proliferating cells tend to exhibit a higher level of PpIX than normal cells after ALA incubation, ALA has been used as a prodrug to enable PpIX fluorescence detection and photodynamic therapy (PDT) of lesion tissues. Extensive studies have been carried out in the past twenty years to explore why some tumors exhibit elevated ALA-mediated PpIX and how to enhance PpIX levels to achieve better tumor detection and treatment. Here we would like to summarize previous research in order to stimulate future studies on these important topics. In this review, we focus on summarizing tumor-associated alterations in heme biosynthesis enzymes, mitochondrial functions and porphyrin transporters that contribute to ALA-PpIX increase in tumors. Mechanism-based therapeutic strategies for enhancing ALA-based modalities including iron chelators, differentiation agents and PpIX transporter inhibitors are also discussed.
Highlights
Considered as pigments of life, porphyrins attract tremendous human curiosity about their chemistry, biosynthesis, role in homeostasis and pathogenesis, and potential as therapeutic agents
Because all porphyrins are biosynthesized from aminolevulinic acid (ALA), an early precursor in the heme biosynthetic pathway that is found in most mammalian cells, ALA can be used to boost the production of endogenous porphyrins for many diagnostic and therapeutic uses
Because PpIX is a metabolite produced in the heme biosynthetic pathway, it is reasonable to assume that the enhanced level of PpIX in tumor cells after ALA incubation is due to changes in the expression or activity of heme biosynthesis enzymes in tumor cells
Summary
Considered as pigments of life, porphyrins attract tremendous human curiosity about their chemistry, biosynthesis, role in homeostasis and pathogenesis, and potential as therapeutic agents. As a class of tetrapyrroles with highly conjugated heterocyclic structure, porphyrins typically have intense absorption of light in the visible range, giving the characteristic red color in animals (due to heme) and green color in plants (due to chlorophyll) It was nearly 150 years ago that hematoporphyrin (HP), a crude porphyrin extract from blood, was first shown to have fluorescence property and about 100 years ago that the fluorescence of HP was found useful for detecting tumors [1]. The photosensitizing property of porphyrins, the ability to convert absorbed light energy into the production of cytotoxic reactive species in the presence of oxygen, was first recognized in the 1900s using HP and extensively studied since the 1970s using partially purified HP preparations [2] These included hematoporphyrin derivatives (HPD) and Photofrin, which led to the world-wide approval of Photofrin-mediated photodynamic therapy (PDT) [1]. We focus this review on the molecular mechanism underlying elevated ALA-PpIX in tumors and mechanism-based therapeutic approaches for enhancing ALA-based modalities with the goal of encouraging further research in these important areas
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