Antineoplastic Activities, Apoptotic Mechanism of Action and Structural Properties of a Novel Silver(I) Chelate

Kareem I.      Batarseh

Abstract

In a previous work, the author has investigated the antimicrobial and cytotoxic properties of tartaric and glutamic acids silver(I) chelates. In a following work, the author has reported on the in vitro cytotoxicity and the mechanism of action of a silver(I) tartaric acid chelate synthesized by the author given the title name Aliargentumycine (AAgM) on hematopoietic malignancies. The in vitro antineoplastic activities of AAgM on solid human breast ductal carcinoma (T- 47D) and disseminated T-cell acute lymphoblastic leukemia (Jurkat) cell lines, its mechanism of action and its structural properties were investigated here. The cytotoxicity results of AAgM were compared to cisplatin, a ubiquitously used platinum-based antitumor drug. Results have indicated that AAgM demonstrated excellent cytotoxicity on both tumor cell lines studied when compared to cis-platin, especially for T-47D. Unlike cisplatin, AAgM was found to exhibit an aberrant triphasic cytotoxicity profile. Phase I exhibited cytotoxicity in the nanoconcentration range, Phase II exhibited no cytotoxicity in the intermediate range, and finally Phase III exhibited cytotoxicity in the microconcentration range. Phase II lacks of cytotoxicity might be an indication of cells reverting back to being nonmalignant in a similar way to 5-Aza-2’- deoxycytidine (decitabine). Quantitative pharmacokinetic-pharmacodynamic analyses were undertaken and were found that AAgM induced significantly better cytotoxic activities than cisplatin between 1.9-30.5 ng/mL while cisplatin did not exhibit any cytotoxicity on T-47D below 122 ng/mL. TUNEL assay was performed and AAgM was found to elicit its antineoplastic activities by apoptosis. X-ray diffraction showed that AAgM is a polymeric chain hydrate structure with no imposed symmetry and the complex around the silver is a monohydrate distorted skew trapezoidal bipyramidal sixcoordinate. AAgM is composed of lipophilic and hydrophilic moieties, making AAgM miscible in both lipids via the tartrate rings and ionic solutions via the water molecules. The results are expected to have significant implications on cancer therapy, especially solid neoplasms, which are exceptionally difficult to treat, and those derived from epithelial and mesenchymal cells, which are not prone to apoptotic responses with cdk inhibitor drugs. Also, the results should be very useful in the design of future novel silver-based antineoplastic drugs.

Keywords: Apoptosis, Cisplatin, Cytotoxicity, Decitabine, Disseminated neoplasms, IC50, Jurkat T-cell acute lymphoblastic leukemia, Mechanism of action, Mesenchymal, Necrosis, Oligodynamic, Pharmacodynamics & pharmacokinetics, Silver(I) tartaric acid chelate, Solid neoplasms, Structure, TUNEL assay, T-47D human breast ductal carcinoma, Trypan blue exclusion method, X-ray crystallography.