The Zn( S -pr-thiosal) ₂ Complex Attenuates Murine Breast Cancer Growth By Inducing Apoptosis and G1/S Cell Cycle Arrest

Abstract

Aim: We investigated the antitumor effects of zinc(II) complex with S-propyl thiosalicylic acid [Zn( S-pr-thiosal)2] in 4T1 murine breast cancer model. Results: The Zn( S-pr-thiosal)2 complex reduced primary tumor growth in vivo and induced tumor cell apoptosis. The Zn( S-pr-thiosal)2 complex disrupted the balance between pro- and antiapoptotic Bcl-2 family members in 4T1 cells and induced G1/S cell cycle arrest. The Zn( S-pr-thiosal)2 complex increased the percentage of p16, p21 and p27 positive 4T1 cells. There was a significantly decrease in expression of STAT3 and its targets c-Myc and cyclin D3 in 4T1 cells treated with the Zn( S-pr-thiosal)2 complex thus contributing to G1/S cell cycle arrest and/or apoptosis. Conclusion: Our data suggest that the Zn( S-pr-thiosal)2 complex restricted tumor growth through induction of mitochondrial-driven apoptosis and suppression of cell cycle progression.

Three metal complexes with a pyridyl Schiff base: cytotoxicity, migration and mechanism of apoptosis

“…Briefly, SMMC-7721 cells were treated with 0, 2.5, 5, and 10 μM complex 2 for 24 h and collected, centrifuged at 1500 rpm for 8 min, and washed twice with cold PBS; the cells were resuspended in binding buffer and incubated on ice with Annexin V-FITC for 15 min in the dark. 34 PI was added before flow cytometry analysis.…”

The Pt(S-pr-thiosal)2 and BCL1 Leukemia Lymphoma: Antitumor Activity In Vitro and In Vivo

“…Salicylates manifest an apoptotic effect in tumor cells by regulating the PTEN/AKT/NF-κB/surviving signaling pathway [ 17 ], and possibly by inducing stress on the endoplasmatic reticulum [ 18 ]. Modification of salicylates [ 19 ] and conjugation of modified salicylates with different metals [ 20 , 21 ] resulted in compounds with stronger antitumor activity. We have previously synthesized and characterized platinum(IV) complexes with S-alkyl derivatives of thiosalicylic acid [ 19 ] and we have shown significant cytotoxic activity of these complexes toward murine leukemia lymphoma cell line (BCL1) and human B-prolymphocytic leukemia (JVM-13) [ 22 ].…”

“…Others also reported stronger antitumor activity of platinum complexes with non-steroidal anti-inflammatory drugs than cisplatin [ 23 ]. Complexes of S-alkyl derivatives of thiosalicylic acid with some other metals, copper and zinc, also have shown marked antitumor activity toward colorectal [ 20 ] and breast cancer [ 21 ] in vitro and in vivo. Copper(II) complexes exhibited pro-apoptotic and anti-proliferative effects, and induced cell cycle disturbances in colorectal cell lines [ 20 ].…”

“…Copper(II) complexes exhibited pro-apoptotic and anti-proliferative effects, and induced cell cycle disturbances in colorectal cell lines [ 20 ]. Zn( S -pr-thiosal)2 complex induced apoptosis of murine breast cancer cell line, inhibited cell proliferation through G1/S cell cycle arrest, and markedly inhibited murine breast cancer growth [ 21 ]. This complex also decreased the expression of STAT3 in murine breast cancer cells and decreased the expression of STAT3 targeted genes [ 21 ].…”

“…Zn( S -pr-thiosal)2 complex induced apoptosis of murine breast cancer cell line, inhibited cell proliferation through G1/S cell cycle arrest, and markedly inhibited murine breast cancer growth [ 21 ]. This complex also decreased the expression of STAT3 in murine breast cancer cells and decreased the expression of STAT3 targeted genes [ 21 ]. The highest cytotoxic potential toward murine B cell leukemia lymphoma cell line, BCL1, showed platinum(IV) complex with S propyl thiosalicylic acid (named Pt( S -pr-thiosal)2 complex), similar to the activity of cisplatin, based on half maximal inhibitory concentration (IC50) values 2.47 ± 0.84 for Pt( S -pr-thiosal)2 versus 2.04 ± 0.79 for cisplatin [ 22 ].…”