Antiproliferative and proapoptotic activity of molecular copper(II) complex of N-1-tosylcytosine

Glavaš-Obrovac, Ljubica; Jukić, Marijana; Mišković, Katarina; Marković, Ivana; Saftić, Dijana; Ban, Željka; Matić, Josipa; Žinić, Biserka (2017) Antiproliferative and proapoptotic activity of molecular copper(II) complex of N-1-tosylcytosine. Journal of Trace Elements in Medicine and Biology . ISSN 0946-672X (In Press)

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Abstract

In an attempt to enhance the previously observed antiproliferative capacity of 1-(p-toluenesulfonyl)cytosine (N-1-tosylcytosine, ligand 1), its copper(II) complex (Cu(1-TsC-N3)2Cl2, complex 2) was prepared and tested in vitro on various carcinoma and leukemia cells. The comparative in vitro studies using the ligand 1, the complex 2, CuCl2 x 2H2O salt (salt 3) and the 1:2 mixture of the salt 3 and ligand 1 (mixture 4) were performed on normal (WI38), human carcinoma (HeLa, CaCo2, MiaPaCa2, SW620), lymphoma (Raji) and leukemia (K562) cell lines. Significantly elevated concentration of the intracellular copper after treatment of K562 cells and HeLa cells during 2 h with complex 2 (7.83 vs. 5.4 times) was detected by atomic absorption spectroscopy. Cytotoxicity was analyzed by MTT assay. We found that antiproliferative capacity of the tested compounds varies (IC50 after 72 h of exposure: 0.6 ×10−6 M to > 100 ×10−6 M). Leukemia and lymphoma cells were found the most sensitive to complex 2 which showed more than 100 times higher in vitro activity against K562 cells than ligand 1. Apoptotic morphological changes, an externalization of phosphatydilserine, and changes in the mitochondrial membrane potential of treated cells were found. The caspase-3 activity in HeLa and K562 cells was measured by caspase-3 colorimetric assay kit. Caspase-3 was not activated in the treated K562 cells while salt 3 and the mixture 4 in the HeLa cells significantly increased tested enzyme activity. These findings suggest that copper(II) in the molecular complex 2 by improving entry of the N-1-tosylcytosine 1 into cells increases its antiproliferative capacity. In summary, the present study demonstrated that complex 2 possesses an antileukemic effect on K562 cells, and its anticancer activity was attributed with induction of apoptosis. The exact mechanism of apoptosis induction by complex 2 must be further investigated.

Item Type:	Article
Additional Information:	This work was supported by the Ministry of Science, Education and Sport of Croatia through Grant Nos. 098-0982914-2935, 219-0982914-2176, J.J. Strossmayer University supporting grant VIF-2015-MEFOS-2. Financial support from the Croatian Science Foundation (grant number HRZZ-1477) is gratefully acknowledged.
Uncontrolled Keywords:	N-1-tosylcytosine ; Copper(II) complex ; In vitro antitumor activity; Apoptosis
Subjects:	NATURAL SCIENCES NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry NATURAL SCIENCES > Biology NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Sinteza novih biološki aktivnih derivata nukleobaza i nukleotida- Biserka Žinić 098-0982914-2935 MZOS Mehanizam bioloških učinaka novih malih molekula na stanice tumora čovjeka- Ljubica Glavaš Obrovac 219-0982914-2176 MZOS UNSPECIFIED UNSPECIFIED VUIF-2015-MEFOS-2 UNSPECIFIED Višenamjensko očitavanje DNA / RNA sekundarne strukture molekularnim kemijskim senzorima-DNA/RNA-MolSense Ivo Piantanida IP-2013-11-1477 HRZZ
Depositing User:	Dijana Pavlović Saftić
Date Deposited:	02 May 2018 12:46
URI:	http://fulir.irb.hr/id/eprint/4018
DOI:	10.1016/j.jtemb.2017.10.009

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