Copper complexes as prospective anticancer agents: in vitro and in vivo evaluation, selective targeting of cancer cells by DNA damage and S phase arrest
Authors: Sethu Amuthakala
Raju Senthil Kumar
Aziz Kalilur Rahiman
Dharmasivam Mahendiran
Nattamai S P Bhuvanesh
Journal: RSC Advances (2018)
Discipline: CHEMISTRY
Keywords: bis(thiosemicarbazone); copper(i) complexes; molecular structure; intercalative mode; CT-DNA
Affiliations: Post-Graduate and Research Department of Chemistry, The New College (Autonomous), Chennai 600 014, India, Department of Chemistry, Texas A & M University, College Station, USA, Department of Pharmaceutical Chemistry, Swamy Vivekanandha College of Pharmacy, Tiruchengodu 637 205

Abstract:  A series of six new bis(thiosemicarbazone)copper(i) complexes of the type [Cu(L1-6)2Cl] (1-6) have been synthesized and characterized. The molecular structure of the ligand L4 was determined by the single crystal XRD method. All the complexes adopted trigonal planar (Y-shaped) geometry. All the complexes strongly bind with CT-DNA via intercalative mode, which was further supported by molecular docking studies. Further, the complexes were effectively bind with BSA as observed by UV-Vis and fluorescence spectra. All the complexes effectively cleave pBR322 DNA through hydrolytic pathway as evidenced from T4 ligase experiments. All the complexes interact with the anticancer receptor focal adhesion kinase (FAK) via electrostatic, van der Waals, hydrogen bonding, œÉ-œÄ and œÄ-œÄ interactions. In vitro cytotoxicity of the complexes were assessed by MTT assay against four cancer cell lines such as human breast adenocarcinoma (MCF-7), cervical (HeLa), epithelioma (Hep-2) and Ehrlich ascites carcinoma (EAC), and two normal cell lines namely normal human dermal fibroblasts (NHDF) and L6 myotubes with respect to the commercially used anticancer drug cisplatin. All the complexes induce apoptosis in EAC cells, which was confirmed by AO/EB, Hoechst 33258 and PI staining methods. The complexes block cell cycle progression of EAC cells in S phase (DNA synthesis). The cellular uptake studies confirmed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. In the in vivo anticancer studies, the complexes significantly reduce the tumour volume in female Swiss albino mice. Overall, our results ensure the role of thiosemicarbazone-based copper(i) complexes as prospective anticancer agents, induction of apoptosis and S phase arrest with the mitochondrial controlled pathway. 

Retracted: No

PubPeer comments:
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  Clear signs of western blot image manipulation in Figure 4 , 
  Further signs of western blot image manipulation in Figure 4. , 
  Signs of western blot image manipulation in Figure 7. , 
  Further signs of western blot image manipulation in Figure 7. , 
 #2 Came across this independently. Figure 2a.  , 
  Another bold blot recycling in Figure 1. , 
 Fig 7  (c) Colon tumour, pancreatic tumour and matched normal tissue were surgically removed and homogenized, and proteins were extracted. Samples (100 mg) were analyzed by immunoblotting for HIF-1a, Phospho-Ser15 p53, total p53, b-actin, p21 14-3-3s, PUMA and Bax.  Unexpected similarity of HIF-1a in matched-normal lanes 1 and 2, and 3 and 4. Shown here with higher contrast:  UPDATE: Come to think of it, Matched-normal lanes 5 and 6, and 7 and 8 are equally similar.  After all that, I have concerns for Phospho-Ser15 p53 in Tumour lanes 5, 7, 8. , 
 Please compare Figure 6(c) *[above]* with *[below]* Figure 1A from [Hill et al {2011)] .  , 
 In Figure 6, not only beta-actin is duplicated, but also Bax!  , 
 Yet another blot re-use in Figure 4, supposedly to depict p21 upregulation induced by irradiation in 2 different cell types...  , 
  , 
 The same band appears twice in Figure 2 of this paper and twice on the Oncotarget 2011 paper to be RETRACTED. https: pubpeer.com publications 8A3553A6E3588DA79EC450A57E1CE5  ,