Metal complexes in cancer therapy &amp;ndash; an update from drug design perspective

Ndagi, Umar; Mhlongo, Ndumiso N.; Soliman, Mahmoud E. S.

doi:10.2147/dddt.s119488

Cited by 750 publications

(545 citation statements)

References 84 publications

(214 reference statements)

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“…1 B ). We also evaluated the effects of carboplatin and oxaliplatin, both platinum-based cytotoxic agents that form types of DNA lesions similar to those formed by cisplatin, but have a different normal tissue toxicity profile (35, 36). The surviving fractions of IDH1 MUT and IDH1 WT HCT116 cells after 72 h exposure to carboplatin or oxaliplatin were similar, suggesting that IDH1 MUT sensitizes HCT116 cells specifically to cisplatin, but not to carboplatin or oxaliplatin (Fig.…”

Section: Resultsmentioning

confidence: 99%

IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

et al. 2018

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Isocitrate dehydrogenase (IDH1)-1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Mutated IDH1 (IDH1MUT) enzymes consume NADPH to produce d-2-hydroxyglutarate (d-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current study was to investigate the mechanism behind the chemosensitivity of the widely used anticancer agent cisplatin in IDH1MUT cancer cells. Oxidative stress, DNA damage, and mitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks (DSBs), and cell death in IDH1MUT cancer cells, as compared with IDH1 wild-type (IDH1WT) cells. Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effects were abolished by the IDH1MUT inhibitor AGI-5198 and were restored by treatment with d-2HG. Thus, our study shows that altered oxidative stress responses and a vulnerable oxidative metabolism underlie the sensitivity of IDH1MUT cancer cells to cisplatin.—Khurshed, M., Aarnoudse, N., Hulsbos, R., Hira, V. V. V., van Laarhoven, H. W. M., Wilmink, J. W., Molenaar, R. J., van Noorden, C. J. F. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.

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Section: Resultsmentioning

confidence: 99%

IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

et al. 2018

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“…Cisplatin, carboplatin and oxaliplatin, the main platinum derivatives used in clinic, share similarities in their structure but also have differences in their mode of action (transport or DNA modifications for example) and are not used for the treatment of the same types of cancers (Table 1). CTR1 [58] ATP7B [60] Passive absorption [61] CTR1 [58,60] OCT1, OCT2 [60] Na + , K + -ATPase pump [60] MATEs [62] DNA Adducts Intra-strand and less frequently inter-strand connections [60] Fewer intra-strand and less frequently inter-strand connections than with cisplatin at equimolar concentrations [60,63] Intra and inter-strand connections more stable and inducing a more important DNA distortion [60] Repair Mechanisms NER and MMR [64,65] NER and MMR [65] NER [65] Type of Cancer Ovary, testis, bladder, colon, rectum, lung or head and neck cancers [66] Ovary, lung and ENT Reduced efficacy in testis, bladder and epidermoid head and neck cancers [67] Stage II/III colon cancers, metastatic colorectal cancers and NSCLCs [68] Side Effects Nausea, vomiting, nephrotoxicity, myelosuppression (thrombocytopenia, leucopenia, anemia) and peripheral sensory neuropathy (ototoxicity) [64] Less important neurotoxicity and ototoxicity than cisplatin Serious myelosuppression strong thrombocytopenia, neutropenia and anemia [60,66] Sensorial neuropathy but no hepatic or kidney toxicity [69] 3.1. Cisplatin…”

Section: Main Platinum Derivatives Used In Cancer Treatmentmentioning

confidence: 99%

Platinum Derivatives Effects on Anticancer Immune Response

et al. 2019

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Along with surgery and radiotherapy, chemotherapeutic agents belong to the therapeutic arsenal in cancer treatment. In addition to their direct cytotoxic effects, these agents also impact the host immune system, which might enhance or counteract their antitumor activity. The platinum derivative compounds family, mainly composed of carboplatin, cisplatin and oxaliplatin, belongs to the chemotherapeutical arsenal used in numerous cancer types. Here, we will focus on the effects of these molecules on antitumor immune response. These compounds can induce or not immunogenic cell death (ICD), and some strategies have been found to induce or further enhance it. They also regulate immune cells' fate. Platinum derivatives can lead to their activation. Additionally, they can also dampen immune cells by selective killing or inhibiting their activity, particularly by modulating immune checkpoints' expression.Cell death is characterized by morphological alterations that have been historically used by The Nomenclature Committee on Cell Death (NCCD) to classify this cellular process into three different forms: type I or apoptosis, type II or autophagy, and type III or necrosis. Although limited, this morphological classification remains widely used, independently of essential molecular aspects of the cell death process. New NCCD classifications focus on molecular mechanisms and on the biochemistry of intracellular signalization effectors. Currently, it is clear that connections and overlaps exist between the different types of cell death. The majority of chemotherapeutic drugs are known to induce apoptosis or necrosis. Engagement of a particular type of cell death depends on the stress type, interaction between induction factors, genetic cell background, organelle content and enzymatic proteins arsenal [3,4].The action of chemotherapy relies not only on its cytotoxic effect on cancer cells, but also on its ability to affect immune cells.

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“…It has been noticed that metal ions have considerable effect on the antibacterial and antifungal activities of antibiotics . Similarly metal ions are famous for their antitumor activity . So the combination between N‐(2‐Aminoethyl)‐1,3‐Propanediamine (AEPD) as N‐donor ligand and some transition metals [Cu (II), Ni (II), Mn (II), Zn (II), Cd (II) and Rh (III)] may generate new complexes which have effective biological, antitumor and antioxidant properties.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant, Antimicrobial and Antitumor Studies of Transition Metal Complexes Derived from N‐(2‐Aminoethyl)‐1,3‐Propanediamine with DFT Calculations and Molecular Docking Investigation

Khalaf‐Alla

2020

Applied Organom Chemis

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New expected biologically active complexes for some of the first (Mn (II), Ni (II), Cu (II) and Zn (II)) and second (Rh (III) and Cd (II)) transitional metals rows with N‐(2‐Aminoethyl)‐1,3‐propanediamine as a ligand (AEPD)have been synthesized. All synthesized complexes were formed with 1:1 (metal: AEPD) stoichiometry except Ni (II) 1:2 (Ni: AEPD). The compounds were characterized by different analysis tools such as; elemental analysis, Fourier transform infrared (FTIR), 1H‐NMR, mass spectra, thermal analysis, electronic spectra, magnetic measurement and molar conductance techniques. AEPD ligand interacted with all metal ions as tridentate ligand by using the nitrogen atoms. On the other hand, density functional theory (DFT) calculations have been performed to confirm the optimized geometrical structures for both AEPD and its complexes. Furthermore, coordination compounds were screened for their potential antibacterial activities against six pathogenic bacteria as well as one kind of fungi in comparison to standard antibiotics by agar well diffusion method. The results show that most of the complexes exhibit antibacterial and antifungal activities against these organisms. Rh (III)‐AEPD complex exhibited the strongest antibacterial effect followed by the Cd (II) complex but as antifungal agents Cd (II) was the first and the second was Rh (III). Also, the anticancer activity was screened for these metal complexes against growth of human liver cancer HEPG2 tumor cell line and this inhibition activity of Cd (II) chelate was noticed to be more active with lowest IC50 than that of all other synthesized complexes. Unfortunately, Mn (II) and Rh (III) chelates lacked anticancer activity. The docking active sites interactions were evaluated using the selected protein for anticancer activity. Finally, antioxidant activity was studied. Mn (AEPD) showed maximum activity followed by complex of Rh (III).

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Metal complexes in cancer therapy – an update from drug design perspective

Cited by 750 publications

References 84 publications

IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

IDH1‐mutant cancer cells are sensitive to cisplatin and an IDH1‐mutant inhibitor counteracts this sensitivity

Platinum Derivatives Effects on Anticancer Immune Response

Antioxidant, Antimicrobial and Antitumor Studies of Transition Metal Complexes Derived from N‐(2‐Aminoethyl)‐1,3‐Propanediamine with DFT Calculations and Molecular Docking Investigation

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