An in vitro investigation of the mechanism of antitumor activity of anthraquinone derivatives

Prirodni antrahinoni, važna klasa hinonskih jedinjenja, se mogu naći u velikom broju viših biljaka, mahovinama, lišajevima kao i drugim organizmima. Ova hinolna jedinjenja poseduju laksativno, antibiotičko, antiinflamatorno i antipiretičko kao i antiviralno dejstvo, a njihov potencijal u tretmanu kancera, i inhibiciji proliferacije i metastaziranja malignih ćelija ih čini jednom od najzanimljivijih grupa jedinjenja u razvoju novih terapeutika. Njihov mehanizam dejstva podrazumeva učešće u metaboličkim procesima, oksidativnoj fosforilaciji, interkalalaciju u DNK i RNK molekule, inhibiciju telomeraze i topoizomeraze II. Najpoznatija podgrupa ove klase jedinjenja su antraciklini, antrahinonski antibiotici. Antraciklini kao što su doksorubicin i daunorubicin imaju izuzetno široku primenu u terapiji kancera, mada su izuzetno kardiotoksični. Tiosemikarbazoni predstavljaju grupu iminskih derivata koji sadrže atom sumpora u svom molekulu, i odlikuje ih izuzetna sposobnost helacije jona metala. Odlikuje ih antiviralno, antibakterijsko, antifungalno, kao i citotoksično i antiproliferativno dejstvo. Halkoni su prekursori flavonoida i izoflavonoida, grupa jedinjenja sa velikim terapeutskim potencijalom, i prisutni su u prirodnim izvorima kao što su voće, začinsko bilje i čajevi. Za njih je utvrđeno da poseduju antioksidativni, antibakterijski, antimalarijski, antiviralni, antihiperglikemijski i antitumorski efekat. Cilj ovog projekta je ispitivanje grupe od trinaest novosintetisanih derivata antrahinona, i analiza njihovih molekularnih mehanizama. Ova jedinjenja su dizajnirana sa ciljem da im se poboljša aktivnost i specifičnost u odnosu na prirodne derivate koji su trenutno u upotrebi. Devet jedinjenja ove grupe predstavljaju antrahinonske tiosemikarbazone, dok su četiri halkonski antrahinoni. Prvi korak u istraživanju je predstavljalo određivanje potencijalnog antitumorskog dejstva derivata antrahinona prema sedam malignih ćelijskih linija poreklom iz različitih tipova kancera. Selektivnost u nivou toksičnog dejstva određena je uz pomoć eksperimenata na uspostavljenoj liniji normalnih humanih ćelija...Naturally occuring anthraquinones, an important class of quinone compounds, are numerous in plants, moss, lichen and other organizms. These quinol compounds posses laxative, antibiotic, antiinflamatory, antipyretic and antiviral properties, and their potential for cancer treatment and inhibition of proliferation and metastasis of malignant cells is what makes them one of the most interesting classes of compounds in cancer drug development field. Their mechanism of action includes involvement in the metabolic processes, oxidativve phosporylation, DNA and RNA intercalation and inhibition of telomerase and topoisomerase II. The most well-known compounds belonging to this class are anthracyclines, anthraquinone antibiotics. Anthracyclines, such as doxorubicin and daunorubicin, are widely used in treatment of cancer, even though they are highly cardiotoxic. Thiosemicarbazones are a class of imine derivatives which posses in their molecule an atom of sulfur. They are characterized by an exceptional ability to chelate metal ions. They have antiviral, antibacterial, antifungal and cytotoxic and antiproliferative activities. Chalcones are flavonoid and isoflavonoid precursors, a class of compounds with a significant therapeutic potential, and they can be found in natural sources like fruit, herbs and teas. It was previously determined that they can have anti-oxidative, antibacterial, antimalarial, antiviral, antihyperglycemic and antitumor effects. The aim of this research is to investigate a group of thirteen newly synthesized anthraquinone derivatives, and to analyze their mechanisms of action. These compounds were designed in a way that aims for increased activity and specificity compared to the currently used natural derivatives. Nine of the thirteen compounds are anthraquinonethiosemicarbazone derivatives, and another four belong to the subgroup of anthraquinonechalcones..

Cytotoxicity and Antimicrobial Activity of the Essential Oil from Satureja montana subsp pisidica (Lamiceae)

The antimicrobial and cytotoxic activities of the essential oil of Satureja montana ssp. pisidica from two localities (mountains Korab and Galicica) were studied. Forty-nine components were identified in the each sample. Oxygenated monoterpene hydrocarbons were the major compounds: carvacrol, thymol, carvacrol methyl ether and beta-linalool. Both tested essential oils showed very high and similar antimicrobial activity. Minimal inhibitory concentrations ranged from 12.5 mu g/mL against S. epidermidis to 50 mu g/mL against P. aerugmosa and C. albicans. The cytotoxic effect of the essential oils was tested against MDA-MB-361, MDA-MB-453, HeLa, LS174 and MRCS cells. The essential oil from Korab demonstrated significantly better results than the oil from Galicica, particularly against HeLa and MDA-MB-453 cell lines, with IC50 values of 63.5 and 72.3 mu g/mL, while the oil from Galicica was the most active on the human epithelial cervical cancer HeLa cells (IC50 99.7 mu g/mL)

Mahonia aquifolium Extracts Promote Doxorubicin Effects against Lung Adenocarcinoma Cells In Vitro

Mahonia aquifolium and its secondary metabolites have been shown to have anticancer potential. We performed MTT, scratch, and colony formation assays; analyzed cell cycle phase distribution and doxorubicin uptake and retention with flow cytometry; and detected alterations in the expression of genes involved in the formation of cell-cell interactions and migration using quantitative real-time PCR following treatment of lung adenocarcinoma cells with doxorubicin, M. aquifolium extracts, or their combination. MTT assay results suggested strong synergistic effects of the combined treatments, and their application led to an increase in cell numbers in the subG1 phase of the cell cycle. Both extracts were shown to prolong doxorubicin retention time in cancer cells, while the application of doxorubicin/extract combination led to a decrease in MMP9 expression. Furthermore, cells treated with doxorubicin/extract combinations were shown to have lower migratory and colony formation potentials than untreated cells or cells treated with doxorubicin alone. The obtained results suggest that nontoxic M. aquifolium extracts can enhance the activity of doxorubicin, thus potentially allowing the application of lower doxorubicin doses in vivo, which may decrease its toxic effects in normal tissues

Supplementary data for article: Marković, V.; Janićijević, A.; Stanojković, T.; Kolundzija, B.; Sladić, D.; Vujčić, M.; Janović, B.; Joksović, L.; Djurdjevic, P. T.; Todorović, N.; et al. Synthesis, Cytotoxic Activity and DNA-Interaction Studies of Novel Anthraquinone-Thiosemicarbazones with Tautomerizable Methylene Group. European Journal of Medicinal Chemistry 2013, 64, 228–238. https://doi.org/10.1016/j.ejmech.2013.03.071

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2013.03.071]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1370

Supplementary data for article: Pantelić, N.; Zmejkovski, B. B.; Kolundžija, B.; Crnogorac, M. Đ.; Vujić, J. M.; Dojčinović, B.; Trifunović, S. R.; Stanojković, T. P.; Sabo, T. J.; Kaluđerović, G. N. In Vitro Antitumor Activity, Metal Uptake and Reactivity with Ascorbic Acid and BSA of Some Gold(III) Complexes with N,N′-Ethylenediamine Bidentate Ester Ligands. Journal of Inorganic Biochemistry 2017, 172, 55–66. https://doi.org/10.1016/j.jinorgbio.2017.04.001

Supplementary material for: [https://doi.org/10.1016/j.jinorgbio.2017.04.001]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2478]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3070

Serum activity of DPPIV and its expression on lymphocytes in patients with melanoma and in people with vitiligo

Background: Dipeptidyl peptidase IV, a multifunctional serine protease, is implicated in regulation of malignant transformation, promotion and further progression of cancer, exerting tumor-suppressing or even completely opposite - tumor-promoting activities. The aim of present research was to determine the serum DPPIV activity, as well as the percentages of CD26+ lymphocytes, CD26+ overall white blood cells and the mean fluorescence intensity of CD26 expression on lymphocytes in patients with melanoma, people with vitiligo and in healthy controls. Methods: The activity of DPPIV in serum was determined by colorimetric test. Expression of DPPIV (as CD26) on immunocompetent peripheral white blood cells was done using flow cytometry analysis. Results: Data from our study show for the first time statistically significant decrease: in the serum DPPIV activity, in the percentage of CD26+ overall white blood cells and in the percentage of lymphocytes in patients with melanoma in comparison to healthy control people. In addition, significantly lower serum DPPIV activity was found in the group of patients with melanoma in relation to people with vitiligo too. Conclusion: This study indicates the need for exploring the cause and the importance of the disturbances in the serum DPPIV activity and in the CD26 expression on immunocompetent cells in complex molecular mechanisms underlying the development and progression of melanomaThe authors are grateful to the Ministry of Education and Science of the Republic of Serbia for the financial support (Project 175011)S

Supplementary data for the article: Marković, V.; Debeljak, N.; Stanojković, T.; Kolundžija, B.; Sladić, D.; Vujčić, M.; Janović, B.; Tanić, N.; Perović, M.; Tešić, V.; et al. Anthraquinone-Chalcone Hybrids: Synthesis, Preliminary Antiproliferative Evaluation and DNA-Interaction Studies. European Journal of Medicinal Chemistry 2015, 89, 401–410. https://doi.org/10.1016/j.ejmech.2014.10.055

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2014.10.055]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1903

Supplementary data for article: Marković, V.; Janićijević, A.; Stanojković, T.; Kolundzija, B.; Sladić, D.; Vujčić, M.; Janović, B.; Joksović, L.; Djurdjevic, P. T.; Todorović, N.; et al. Synthesis, Cytotoxic Activity and DNA-Interaction Studies of Novel Anthraquinone-Thiosemicarbazones with Tautomerizable Methylene Group. European Journal of Medicinal Chemistry 2013, 64, 228–238. https://doi.org/10.1016/j.ejmech.2013.03.071

Supplementary material for: [https://doi.org/10.1016/j.ejmech.2013.03.071]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1370

Supplementary data for article: Pantelić, N.; Zmejkovski, B. B.; Kolundžija, B.; Crnogorac, M. Đ.; Vujić, J. M.; Dojčinović, B.; Trifunović, S. R.; Stanojković, T. P.; Sabo, T. J.; Kaluđerović, G. N. In Vitro Antitumor Activity, Metal Uptake and Reactivity with Ascorbic Acid and BSA of Some Gold(III) Complexes with N,N′-Ethylenediamine Bidentate Ester Ligands. Journal of Inorganic Biochemistry 2017, 172, 55–66. https://doi.org/10.1016/j.jinorgbio.2017.04.001

Supplementary material for: [https://doi.org/10.1016/j.jinorgbio.2017.04.001]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2478]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3070