In vitro nephrotoxicity and anticancer potency of newly synthesized cadmium complexes

Selda Abyar,Jonathan M White,Seyed Abolfazl Hosseini-Yazdi,Ali Akbar Khandar,Roya Salehi,O Aizpurua-Olaizola,Motahhareh Shojaei,Rosalinde Masereeuw,Mehrdad Mahkam,Manoe J Janssen,Amer Jamalpoor,Effat Alizadeh

doi:10.1038/s41598-019-51109-9

Abstract

Complexes based on heavy metals have great potential for the treatment of a wide variety of cancers but their use is often limited due to toxic side effects. Here we describe the synthesis of two new cadmium complexes using N(4)-phenyl-2-formylpyridine thiosemicarbazone (L1) and 5-aminotetrazole (L2) as organic ligands and the evaluation of their anti-cancer and nephrotoxic potential in vitro. The complexes were characterized by Single-crystal X-ray data diffraction, 1HNMR, FT-IR, LC/MS spectrometry and CHN elemental analysis. Next, cytotoxicity of these cadmium complexes was evaluated in several cancer cell lines, including MCF-7 (breast), Caco-2 (colorectal) and cisplatin-resistant A549 (lung) cancer cell lines, as well as in conditionally-immortalized renal proximal tubule epithelial cell lines for evaluating nephrotoxicity compared to cisplatin. We found that both compounds were toxic to the cancer cell lines in a cell-cycle dependent manner and induced caspase-mediated apoptosis and caspase-independent cell death. Nephrotoxicity of these compounds was compared to cisplatin, a known nephrotoxic drug, in vitro. Our results demonstrate that compound {2}, but not compound {1}, exerts increased cytotoxicity in MCF-7 and A549 cell lines, combined with reduced nephrotoxic potential compared to cisplatin. Together these data make compound {2} a likely candidate for further development in cancer treatment.

Highlights

Complexes based on heavy metals have great potential for the treatment of a wide variety of cancers but their use is often limited due to toxic side effects
Its intake can lead to cadmium accumulation in the proximal tubules cells (PTC) of the kidney, potentially leading to renal dysfunction[9,10]
To confirm the reduced sensitivity in kidney cells, we evaluated the Annexin V/propidium iodide (PI) staining in conditionally immortalized human proximal tubule epithelial cells (ciPTEC) after exposure to the same concentration (50 μM) of either compound {2} or cisplatin for 24 h

Summary

Introduction

Complexes based on heavy metals have great potential for the treatment of a wide variety of cancers but their use is often limited due to toxic side effects. The complexes were characterized by Single-crystal X-ray data diffraction, 1HNMR, FT-IR, LC/MS spectrometry and CHN elemental analysis Cytotoxicity of these cadmium complexes was evaluated in several cancer cell lines, including MCF-7 (breast), Caco-2 (colorectal) and cisplatinresistant A549 (lung) cancer cell lines, as well as in conditionally-immortalized renal proximal tubule epithelial cell lines for evaluating nephrotoxicity compared to cisplatin. We found that both compounds were toxic to the cancer cell lines in a cell-cycle dependent manner and induced caspase-mediated apoptosis and caspase-independent cell death. For comparison of the efficacy and safety profiles of the new cadmium complexes, cisplatin was used as a reference drug

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