Thiosemicarbazones are important compounds in biological application. Their broad spectrum of biological properties includes antiviral, antifungal and antiproliferative activity. Due to the ability to chelate heavy metals, these compounds have been used extensively in cancer research to study the effects of their inhibition of cell growth. Their mechanism of action includes generation of reactive oxygen within cancer cells, iron chelation, inhibition of the enzyme ribonucleotide reductase (RR) necessary in the synthesis of DNA [1]. Iron is essential for cancer cell proliferation and can also participate in the Fenton reaction to generate reactive oxygen species (ROS).

The generation of reactive oxygen species (ROS) by drugs is associated with loss of intracellular redox potential. Cellular redox potential is largely determined by reduced glutathione (GSH). GSH is important for many cellular biochemical functions including the regulation of gene transcription, as well as the modulation of apoptosis [2]. Reduced GSH is the biological active form that is oxidized to glutathione disulfide (GSSG) during oxidative stress. Changes of the ratio of GSH to GSSG determines the cells fate. Decreases in cellular GSH levels leads to initiation of the Fas receptor activation or mitochondrial apoptosis pathway [3].

Obtained series of novel derivatives thiosemicarbazones, showing the highest antiproliferative activity against human colon carcinoma (HCT116 +/+) have been tested for effects on mitochondrial GSH. The results demonstrated the significant reduction in the cellular levels of glutathione, which is expected effect of cancer therapy.

References:

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

[2] M. L. Circu, T. Y. Aw, “Glutathione and modulation of cell apoptosis.” Biochimica et Biophysica Acta, vol. 1823, pp. 1767–1777, Jun. 2012

[3] M. L. Circu, T. Y. Aw, “Reactive oxygen species, cellular redox systems, and apoptosis.”, Free Radical Biology & Medicine, vol. 48, pp. 749–762, Mar. 2010

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