Copper complexes as prospective anticancer agents: <i>in vitro</i> and <i>in vivo</i> evaluation, selective targeting of cancer cells by DNA damage and S phase arrest

Mahendiran, Dharmasivam; Amuthakala, Sethu; Bhuvanesh, Nattamai; Raju, Senthil Kumar; Rahiman, A. Kalilur

doi:10.1039/c8ra00954f

Cited by 69 publications

(44 citation statements)

References 63 publications

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“…Copper is indispensable in the angiogenesis process, the administration of copper sequestering agents as an antitumor approach is under evaluation [5][6][7]. During the angiogenesis process, copper translocates from intracellular to extracellular space [55].…”

Section: Discussionmentioning

confidence: 99%

“…Angiogenesis sustains tumor and metastasis development [1], and high levels of copper are found in the plasma of patients affected by tumors [2][3][4]. The reasons for this elevation remain unclear, however, the administration of copper sequestering agents as an antitumor approach is under evaluation [5,6]. Recently, a study regarding the evaluation of novel copper-based complexes was conducted.…”

Section: Introductionmentioning

confidence: 99%

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The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

Zimbone

Santoro

Mendola

et al. 2020

IJMS

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Copper plays an important role as a regulator in many pathologies involving the angiogenesis process. In cancerogenesis, tumor progression, and angiogenic diseases, copper homeostasis is altered. Although many details in the pathways involved are still unknown, some copper-specific ligands have been successfully used as therapeutic agents. Copper-binding peptides able to modulate angiogenesis represent a possible way to value new drugs. We previously reported that a fragment (VEGF73-101) of vascular endothelial growth factor (VEGF165), a potent angiogenic, induced an apoptotic effect on human umbilical vein endothelial cells. The aim of this study was to investigate the putative copper ionophoric activity of VEGF73-101, as well as establish a relationship between the structure of the peptide fragment and the cytotoxic activity in the presence of copper(II) ions. Here, we studied the stoichiometry and the conformation of the VEGF73-101/Cu(II) complexes and some of its mutated peptides by electrospray ionization mass spectrometry and circular dichroism spectroscopy. Furthermore, we evaluated the effect of all peptides in the absence and presence of copper ions by cell viability and cytofuorimetric assays. The obtained results suggest that VEGF73-101 could be considered an interesting candidate in the development of new molecules with ionophoric properties as agents in antiangiogenic therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

Zimbone

Santoro

Mendola

et al. 2020

IJMS

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“…The in vitro and in vivo studies of copper(I) complexes of bis(acetophenone thosemicarbazone)/bis(p-substituted acetophenone thiosemicarbazone) (C 42 -C 47 ) (Fig. 5) against cancer cell lines-MCF-7 (human breast adenocarcinoma), HeLa (cervical), Hep-2 (epithelioma), Ehrlich ascites carcinoma (EAC) and normal cell lines; NHDF (normal human dermal fibroblasts) and L6 myotubes showed their anticancer activity at the micro molar concentration (IC 50 10.9-18.9 μM, MCF-7) as comparable to cisplatin (IC 50 12.1 μM, MCF-7) by DNA (pBR322) cleavage through a hydrolytic pathway and caspase-dependent-mitochondrial-mediated cell apoptosis via ROS production (Mahendiran et al, 2018a). These complexes were able to reduce the volume of tumors in female Swiss albino mice by inducing cell apoptosis and S phase (DNA synthesis) arrest with the mitochondrial controlled pathway.…”

Section: Bis(acetophenone Thosemicarbazone) Copper(i) Complexesmentioning

confidence: 99%

“…These complexes were able to reduce the volume of tumors in female Swiss albino mice by inducing cell apoptosis and S phase (DNA synthesis) arrest with the mitochondrial controlled pathway. The complexes strongly killed the EAC tumor cell line with no toxicity against normal cells (Mahendiran et al, 2018a). (1-methyl-1H-benzo[d]imidazol-2-yl)benzene)] against A549 (human lung), A375 (melanoma), MCF-7 (breast), LoVo (colon adenocarcinoma), HeLa cervical cancer cell lines, and HEK293 (non-malignant fibroblasts) showed higher antitumor activity (IC 50 0.98-21.57 μM) than that of the standard drug cisplatin (IC 50 2.19-23.87 μM) and their corresponding ligand (IC 50 >100 μM).…”

Section: Bis(acetophenone Thosemicarbazone) Copper(i) Complexesmentioning

confidence: 99%

Anticancer Potency of Copper(I) Complexes Against a Range Cancer Cell Lines: A Review

Singh

Yadav

2021

J. Inst. Sci. Tech.

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The copper(I) complexes of N,N-diimine, N,O- and/or N, S-bidentate systems perform significant dose-dependent anticancer activity toward various cell lines viz. MCF-7, LNCap, PSN-1, A431, BxPC3, H157, A2780, HeLa, MDA-MB231, MGC-803 etc. The copper(I) complexes can cross the cellular plasmalemma that results in the accumulation of copper ion in the cancer cells, exhibit significant anticancer effect and overcome the multidrug resistance because these can slightly induce the DNA cleavage as a result of limited generation of reactive oxygen species (ROS). Copper(I) complexes exhibit significantly higher broad-spectrum antiproliferation and cell apoptosis via mitochondrial pathway than that of their corresponding Cu(II), Co(II), Pd(II), and Ni(II) complexes. The copper(I) complexes inhibit the cancer cells not only via ROS generation but also via DNA interactions possibly by attacking the sugar-phosphate backbone of DNA due to their oxidative and partial dissociation behavior. Copper(II/I) complexes are also able to cleave DNA by hydrolytic pathway and induce caspase-dependent-mitochondrial-mediated cell apoptosis by ROS production or blocking the progression of cell cycles. In many cases, the modification in organic moiety and the placement of electronegative substituent near the metallic center of complexes have been found to enhance their anticancer potency in a significant manner. Thus copper(I) complexes may be used as the better anticancer drugs with multiple modes of action compared to the copper(II) complexes due to having oxidative behavior and generation of empty site on copper(I) ion during partial dissociation.

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“…De igual manera Mahendiran y colaboradores sintetizaron una familia de cuatro complejos de cobre (II) con tiosemicarbazonas y los evaluaron en las líneas de fenotipo normal, como NHDF y miotubos L6. Nuevamente los complejos tuvieron un efecto diferencial entre ligandos y complejos y fueron más citotóxicos sobre las células MCF-7, HeLa, Hep2 y EAC [334].…”

Section: Figura 53-20 Resultados Del Ensayo Cometa En Células A549 Eunclassified

Screening de metalofármacos derivados de N-heterociclos y metales de transición en cultivos celulares 2D y 3D según sus efectos antitumorales

Vargas¹,

Fernando²

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El desarrollo de fármacos es un proceso complejo el cual inicia con la identificación de compuestos que muestran actividad biológica en un ensayo de tamizaje. La mayoría de los medicamentos que están en uso clínico son el resultado de un proceso de investigación muy complejo. Por ello, es necesaria la unión de esfuerzos de diferentes disciplinas científicas para descubrir y desarrollar medicamentos con efectos clínicos benéficos y efectos secundarios mínimos. Se estima que de cada 9.000 moléculas biológicamente activas solo una tiene uso clínico. Los resultados presentados en este trabajo de tesis doctoral indican que los complejos de cobre(II) estudiados ejercen sus efectos citotóxicos a través de mecanismos de muerte que conllevan a un aumento del estrés oxidativo, una disminución de los niveles de GSH con el consecuente arresto del ciclo celular y/o la inducción de apoptosis. Asimismo, estos compuestos inducen genotoxicidad provocada por un daño oxidativo a nivel del ADN. En modelos tridimensionales de células tumorales, también se pudieron encontrar efectos citotóxicos y sobre la invasión celular. Por otro lado, cabe destacar que la eficacia de los compuestos tamizados aumenta con la cantidad admitida de cobre que está asociada a su vez con la lipofilicidad (y con las estructuras químicas). Los complejos ternarios con 2,2´biquinolina, SMTCu y SDQCu, resultaron ser los complejos más prometedores, ya que no solo se destacan del resto de los complejos de cobre de las otras familias estudiadas en forma individual sino incluso supera a Cu6MQ en mezcla uno a uno con Zn6MQ. Asimismo, de los complejos de cobre con sulfonamidas, solo SDQCu, muestra un efecto sinérgico en un tratamiento combinado con radioterapia.

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Copper complexes as prospective anticancer agents: in vitro and in vivo evaluation, selective targeting of cancer cells by DNA damage and S phase arrest

Abstract: The thiosemicarbazone-based copper(i) complexes causing S phase arrest and apoptosis involving the mitochondrial controlled pathway has been investigated.

Cited by 69 publications

References 63 publications

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

The Ionophoric Activity of a Pro-Apoptotic VEGF165 Fragment on HUVEC Cells

Anticancer Potency of Copper(I) Complexes Against a Range Cancer Cell Lines: A Review

Screening de metalofármacos derivados de N-heterociclos y metales de transición en cultivos celulares 2D y 3D según sus efectos antitumorales

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