An anticancer Ti(IV) complex increases mitochondrial reactive oxygen species levels in relation with hypoxia and endoplasmic-reticulum stress: A distinct non DNA-related mechanism

Shpilt, Zohar; Melamed-Book, Naomi; Tshuva, Edit Y.

doi:10.1016/j.jinorgbio.2023.112197

Cited by 9 publications

(6 citation statements)

References 74 publications

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“…Indeed, oncogenic mutations (e.g., KRAS and BRAF ) within the MAPK network are involved in pathogenesis of a significant number of human tumors. These observations are consistent with Shpilt et al (2023) and Pesch et al (2016) whose Ti complexes possess a non-DNA mechanism of action, evoking G2/M cell cycle arrest, causing ER stress, ROS, mitochondrial disruption, and apoptosis. Allison et al recently (2021) demonstrated selective inhibition of multiple kinases by metal (Zn and Cu) complexes in human carcinoma cell lines.…”

Section: Discussionsupporting

confidence: 91%

Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents

Musa,

Abid,

Bradshaw

et al. 2024

J. Med. Chem.

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The need for anticancer therapies that overcome metallodrug resistance while minimizing adverse toxicities is targeted, herein, using titanium coordination complexes. Octahedral titanium(IV) trans,mer-[Ti{R1N(CH2–2-MeO-4-R1-C6H2)2}2] [R1 = Et, allyl, n-Pr, CHO, F, CH2(morpholino), the latter from the formyl derivative; R2 = Me, Et; not all combinations] are attained from Mannich reactions of commercial 2-methoxyphenols (27–74% overall yield, 2 steps). These crystalline (four X-ray structures) Ti(IV)-complexes are active against MCF-7, HCT-116, HT-29, PANC-1, and MDA-MB-468 cancer cell lines (GI50 = 0.5–38 μM). Their activity and cancer selectivity (vs nontumor MRC-5 cells) typically exceeds that of cisplatin (up to 16-fold). Proteomic analysis (in MCF-7) supported by other studies (G2/M cell cycle arrest, ROS generation, γH2AX production, caspase activation, annexin positivity, western blot, and kinase screens in MCF-7 and HCT-116) suggest apoptosis elicited by more than one mechanism of action. Comparison of these data to the modes of action proposed for salan Ti(IV) complexes is made.

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Section: Discussionsupporting

confidence: 91%

Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents

Musa,

Abid,

Bradshaw

et al. 2024

J. Med. Chem.

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“…Therefore, the cells experienced oxidative stress with elevated amounts of ROS, and thus the cells were unable to resolve the oxidative stress, which ultimately led to apoptosis. Above all, it was identified that the main cellular MoA of PhenolaTi was the creation of ER stress under hypoxia, and generation of ROS in the mitochondria and ER was pointed out as the possible target organelle for the cell death mechanism of PhenolaTi …”

Section: Metallotherapeutics Toward Glutathione Depletion and Cancer ...mentioning

confidence: 99%

Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy

Roy,

Paira

2024

ACS Omega

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The cellular defense system against exogenous substances makes therapeutics inefficient as intracellular glutathione (GSH) exhibits an astounding antioxidant activity in scavenging reactive oxygen species (ROS) or reactive nitrogen species (RNS) or other free radicals produced by the therapeutics. In the cancer cell microenvironment, the intracellular GSH level becomes exceptionally high to fight against oxidative stress created by the production of ROS/RNS or any free radicals, which are the byproducts of intracellular redox reactions or cellular respiration processes. Thus, in order to maintain redox homeostasis for survival of cancer cells and their rapid proliferation, the GSH level starts to escalate. In this circumstance, the administration of anticancer therapeutics is in vain, as the elevated GSH level reduces their potential by reduction or by scavenging the ROS/RNS they produce. Therefore, in order to augment the therapeutic potential of anticancer agents against elevated GSH condition, the GSH level must be depleted by hook or by crook. Hence, this Review aims to compile precisely the role of GSH in cancer cells, the importance of its depletion for cancer therapy and examples of anticancer activity of a few selected metal complexes which are able to trigger cancer cell death by depleting the GSH level.

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“…23 The exact mechanism of action of phenolaTi and related Ti(IV) complexes is still largely under investigations, with previous observations pointing to the participation of endoplasmic reticulum-(ER-) stress and hypoxia in tumor demise. [27][28][29][30] Several metal complexes have been shown to possess antibacterial activities. 31,32 In particular, it has been reported that Ti-based compounds inhibit the growth of Escherichia coli, Salmonella typhimurium, and Pseudomonas aeruginosa, 33 and TiO 2 nanoparticles generate reactive oxygen species which are lethal to bacteria.…”

Section: Introductionmentioning

confidence: 99%

“…23 The exact mechanism of action of phenolaTi and related Ti( iv ) complexes is still largely under investigations, with previous observations pointing to the participation of endoplasmic reticulum- (ER-) stress and hypoxia in tumor demise. 27–30…”

Section: Introductionmentioning

confidence: 99%

Titanium complexes affectBacillus subtilisbiofilm formation

et al. 2023

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An anticancer Ti(IV) complex increases mitochondrial reactive oxygen species levels in relation with hypoxia and endoplasmic-reticulum stress: A distinct non DNA-related mechanism

Cited by 9 publications

References 74 publications

Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents

Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents

Glutathione Depletion and Stalwart Anticancer Activity of Metallotherapeutics Inducing Programmed Cell Death: Opening a New Window for Cancer Therapy

Titanium complexes affectBacillus subtilisbiofilm formation

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