The subject of interest of this presentation is a group of derivatives of thiosemicarbazones, which are tridentate active iron chelators with high Fe mobilization efficacy and low toxicity [1]. Iron is a common factor participates in a variety of important processes such DNA synthesis, electron transport, oxygen delivery and erythropoiesis. This element is a component of numerous enzymes catalyzing redox processes and taking part in cellural respiration. The mechanism of action of thiosemicarbazone derivatives includes generation reactive oxygen species (ROS) and iron chelation, which is required to rapidly proliferating cancer cells [2]. Cancer cells, when compared with normal, have increased demand for iron which makes them more susceptible to the effects of its depletion. As a consequence the cancer cells treating with compounds of high affinity to iron are arrested at the G1/S interface [3]. However these compounds have other possible mechanisms of action as inhibition of ribonucleotide reductase - mammalian enzyme which playing crucial role in the DNA replication and repair. In addition, depletion of iron affects the regulation of important genes such as BNIP3 and NDRG1, which are crucial for triggering apoptosis of cancer cells. Thiosemicarbazones are an attractive material for the study of anticancer therapy because of their multi-targeted mechanism of action [4]. Photochemical studies included the implementation of the absorbance and fluorescence spectra measurements of thiosemicarbazones and biophysical investigation of the effect of iron chelators on the generation of ROS. This was achieved by flash photolysis of the studied compounds. Antiproliferative activity was estimated on HCT 116 cell line (human colon carcinoma) with normal p53+/+ and suppresed p53 protein functionality (p53-/-) to examined whether the p53 status of this cell line altered their response to the thiosemicarbazone analogues. Protein p53 is the important tumor supresor involved various mechanisms of defence against tumor in healthy cells. Anticancer activity was evaluated using MTS - reduction colorimetric survival assay. Additionally we checked an effectiveness of thiosemicarbazones on the survival and proliferation of cells using clonogenic assay. Fluorescence microscopy was used to record images the morphology of cells after incubation with the investigated compounds. We examined penetration into the cell and changes in cytoskeletal structure and cell organelles. An innovative approach may be the use of thiosemicarbazone derivatives as anciliary drug in photodynamic therapy. PDT is a method characterized by low invasive treatment, and high selectivity relative to normal cells. Nowadays it’s an attractive strategy for treating various ailments, including skin cancer. The essence of PDT is to produce singlet oxygen and free radicals in the reaction, of photosensitizer with light of appropriate wavelength. The condition of photodynamic reaction is the presence of oxygen. Formed reactive oxygen species trigger chain reactions in the cell, causing various types of damage leading to the destruction of the affected tissue. As photosensitizer may be used (Photofrin®) unfortunately its use is difficult due to unfavorable pharmacokinetic parameters. As remedy ALA-PDT therapy has been proposed which involves the administration of 5-aminolevulinic acid, which is an endogenic precursor of protoporfirin IX [5]. The accumulation of photosensitizer in diseased tissue is extremely important, because the exposure does not cause damage to healthy tissue. The difference in accumulation of PpIX in diseased and healthy tissue is caused by differences in activities of enzymes regulating the formation of PpIX (porphobilinogen deaminase) and heme (ferrochelatase) [6]. The use of chelators allow to increase the intensity of PpIX accumulation in the tumor, by blocking the last steps of heme formation. In our approach novel highly active against proliferating cells iron chelators are combined with ALA-PDT and tested as multitargeted anticancer therapy in vitro. This simple strategy based on drugs already in use or under clinical trials as well as novel compounds is appealingly effective during this early step study.

References:

[1] D. S. Kalinowski, P. C. Sharpe, P. V. Bernhardt, and D. R. Richardson, “Structure-activity relationships of novel iron chelators for the treatment of iron overload disease: the methyl pyrazinylketone isonicotinoyl hydrazone series.,” Journal of Medicinal Chemistry, 51, 2, 331-44, 2008.

[2] D. R. Richardson, D. S. Kalinowski, S. Lau, P. J. Jansson, and D. B. Lovejoy, “Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents.,” Biochimica et Biophysica Acta, 1790, 7, 702-17, 2009.

[3] M. Whitnall, J. Howard, P. Ponka, and D. R. Richardson, “A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics.,” Proceedings of the National Academy of Sciences of the United States of America, 103, 40, 14901-6, 2006.

[4] Y. Yu et al., “Thiosemicarbazones from the old to new: iron chelators that are more than just ribonucleotide reductase inhibitors.,” Journal of Medicinal Chemistry, 52, 17, 5271-94, 2009.

[5] S. Langer et al., “Active and higher intracellular uptake of 5-aminolevulinic acid in tumors may be inhibited by glycine,” Journal of Investigative Dermatology, 112, 5, 723–728, 1999.

[6] A. Pye and A. Curnow, “Direct comparison of delta-aminolevulinic acid and methyl-aminolevulinate-derived protoporphyrin IX accumulations potentiated by desferrioxamine or the novel hydroxypyridinone iron chelator CP94 in cultured human cells.,” Photochemistry and Photobiology, 83, 3, 766-73, 2007.

Anna Mrozek-Wilczkiewicz appreciates the support of UPGOW fellowship and NCN grant N405/068440 Maciej Serda was supported by a TWING fellowship and NCN grant DEC-2011/01/N/NZ4/01166

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