Iron Chelators in Photodynamic Therapy Revisited: Synergistic Effect by Novel Highly Active Thiosemicarbazones

Abstract

In photodynamic therapy (PDT), a noninvasive anticancer treatment, visible light, is used as a magic bullet selectively destroying cancer cells by a photosensitizer that is nontoxic in the dark. Protoporphyrin IX (PpIX) is a natural photosensitizer synthesized in the cell, which is also a chelating agent that if bonded to Fe 2+ forms heme, a central component of hemoglobin. Therefore, xenobiotic iron chelators can disturb iron homeostasis, increasing the accumulation of PpIX, obstructing the last step of heme biosynthesis, and enhancing PDT efficiency. However, the attempts to use this promising idea have not proved to be hugely successful. Herein, we revisited this issue by analyzing the application of iron chelators highly toxic in the dark, which should have higher Fe 2+ affinity than the nontoxic chelators used so far. We have designed and prepared thiosemicarbazones (TSC) with the highest dark cellular cytotoxicity among TSCs ever reported. We demonstrate that compound 2 exerts powerful PDT enhancement when used in combination with 5-aminolevulinic acid (ALA), a precursor of PpIX.

4′‐Phenyl‐2,2′:6′,2′′‐terpyridine Derivatives Containing 1‐Substituted‐2,3‐Triazole Ring: Synthesis, Characterization and Anticancer Activity

“…An example of such compounds are bispyridine iron chelators that have been widely investigated for anticancer activity. [27][28][29][30][31] Chelating metal ions as a mechanism of action may increase selectivity as cancer cells often have a higher level of biologically relevant metal as iron, copper, and zinc. In this regards, iron and especially copper for its ability to generate reactive oxygen species seems to be valuable.…”

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

“…Thiosemicarbazones (TSCs) are sulfur-containing organic substances whose biological properties have been extensively studied [1][2][3][4][5][6][7][8], in particular their activities against microbial diseases as malaria, small-pot, influenza, leishmaniasis or chagas [9][10][11][12][13][14], neurological pathologies [15,16] and cancer [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. Different biological targets have been identified, like DNA [37][38][39], RNA [40] and several enzymes as RNA-dependent DNA polymerases [41], xanthine oxidoreductase [42], thioredoxin reductase [43,44], topoisomerase IIa [45][46][47] or s...…”

Chemical approaches for the enhancement of 5-aminolevulinic acid-based photodynamic therapy and photodiagnosis

“…Finally, Mrozek-Wilczkiewicz et al 72 have reported the concept of enhancing ALA-PDT using thiosemicarbazone (TSC) iron chelators, which have been previously developed as standalone anticancer agents (Fig. 13).…”