Cytotoxicity and cell death mechanisms induced by the polyamine-vectorized anti-cancer drug F14512 targeting topoisomerase II

Various Pt IV diazides have been investigated over the years as light-activatable prodrugs that interfere with cell proliferation, accumulate in cancer cells and cause cell death. The potencies of the complexes vary depending on the substituted amines (pyridine=piperidine>ammine) as well as the coordination geometry ( trans diazide> cis ). Light-activated Pt IV diazides tend to be less specific than cisplatin at inhibiting cancer cell growth, but cells resistant to cisplatin show little cross-resistance to Pt IV diazides. Platinum is accumulated in the cancer cells to a similar level as cisplatin, but only when activated by light, indicating that reactive Pt species form photolytically. Studies show that Pt also becomes attached to cellular DNA upon the light activation of various Pt IV diazides. Structures of some of the photolysis products were elucidated by LC–MS/MS; monoaqua- and diaqua-Pt II complexes form that are reactive towards biomolecules such as calf thymus DNA. Platination of calf thymus DNA can be blocked by the addition of nucleophiles such as glutathione and chloride, further evidence that aqua-Pt II species form upon irradiation. Evidence is presented that reactive oxygen species may be generated in the first hours following photoactivation. Cell death does not take the usual apoptotic pathways seen with cisplatin, but appears to involve autophagy. Thus, photoactivated diazido-Pt IV complexes represent an interesting class of potential anti-cancer agents that can be selectively activated by light and kill cells by a mechanism different to the anti-cancer drug cisplatin.

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Anti-cancer Applications of Titanocene-Functionalised Nanostructured Systems: An Insight into Cell Death Mechanisms

Chemistry - A European Journal ◽

10.1002/chem.201400300 ◽

2014 ◽

Vol 20 (34) ◽

pp. 10811-10828 ◽

Cited By ~ 30

Author(s):

Jesús Ceballos-Torres ◽

Piroska Virag ◽

Mihai Cenariu ◽

Sanjiv Prashar ◽

Mariano Fajardo ◽

...

Keyword(s):

Cell Death ◽

Anti Cancer ◽

Nanostructured Systems ◽

Cell Death Mechanisms ◽

Insight Into

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Regucalcin ameliorates Doxorubicin-induced cytotoxicity in Cos-7 kidney cells and translocates from the nucleus to the mitochondria

Bioscience Reports ◽

10.1042/bsr20211464 ◽

2021 ◽

Author(s):

Noor A Mohammed ◽

Israa Hakeem ◽

Nikolas J Hodges ◽

Francesco Michelangeli

Keyword(s):

Cell Death ◽

Cell Model ◽

Cancer Drug ◽

Kidney Cells ◽

Strongly Correlated ◽

Caspase 9 ◽

Membrane Blebbing ◽

Chemically Induced ◽

Anti Cancer ◽

Liver And Kidney

Doxorubicin (DOX) is a potent anti-cancer drug, which can have unwanted side-effects such as cardiac and kidney toxicity. A detailed investigation was undertaken of the acute cytotoxic mechanisms of DOX on kidney cells, using Cos-7 cells as kidney cell model. Cos-7 cells were exposed to DOX for a period of 24 hours over a range of concentrations and the LC50 was determined to be 7µM. Further investigations showed that cell death was mainly via apoptosis involving Ca2+ and caspase 9, in addition to autophagy. Regucalcin (RGN), a cytoprotective protein found mainly in liver and kidney tissues, was overexpressed in Cos-7 cells and shown to protect against DOX-induced cell death. Subcellular localization studies in Cos-7 cells showed RGN to be strongly correlated with the nucleus. However, upon treatment with DOX for 4 hours, which induced membrane blebbing in some cells, the localization appeared to be correlated more with the mitochondria in these cells. It is yet to be determined whether this translocation is part of the cytoprotective mechanism or a consequence of chemically-induced cell stress.

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CB13, a novel PPARγ ligand, overcomes radio-resistance via ROS generation and ER stress in human non-small cell lung cancer

Cell Death and Disease ◽

10.1038/s41419-020-03065-w ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Tae Woo Kim ◽

Da-Won Hong ◽

Sung Hee Hong

Keyword(s):

Lung Cancer ◽

Cell Death ◽

Er Stress ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Cancer Drug ◽

Small Cell Lung ◽

Pparγ Agonist ◽

Anti Cancer

Abstract Peroxisome proliferator-activated receptor gamma (PPARγ) is a well-known therapeutic target for type 2 diabetes as well as is a potential target for effective anti-cancer drug, since PPARγ ligands such as ciglitazone (Cig) frequently cause cell death in many types of cancer cells and suppress tumor growth. However, many cancer patients acquire chemo-resistance or radio-resistance after chemo or radiotherapy, and it is still unclear. In the difficulty of well-known anti-cancer drugs, we developed a novel PPARγ agonist CB13 (1-benzyl-5-(4-methylphenyl) pyrido [2,3-d]pyrimidine-2,4(1H,3H)-dione) and investigated the anti-cancer effect and cell death mechanism on human non-small cell lung cancer (NSCLC) cells. With anti-cancer effect of Cig, CB13 also causes inhibition of cell growth by decreasing cell viability, increasing the release of LDH, and increasing caspase-3, and caspase-9 activities. CB13 generates reactive oxygen species (ROS) and causes cell death via ER stress in NSCLC and radio-resistant NSCLC cells (A549R and H460R), and a combination of CB13 and radiation induces greater ER stress and cell death when compared to CB13 alone. Taken together, our results suggest that a combination of CB13 and radiation may overcome radio-resistance caused by radiotherapy.

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Neuroprotective Effects of the Anti-cancer Drug Lapatinib Against Epileptic Seizures via Suppressing Glutathione Peroxidase 4-Dependent Ferroptosis

Frontiers in Pharmacology ◽

10.3389/fphar.2020.601572 ◽

2020 ◽

Vol 11 ◽

Author(s):

Ji-Ning Jia ◽

Xi-Xi Yin ◽

Qin Li ◽

Qi-Wen Guan ◽

Nan Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Glutathione Peroxidase ◽

Neuronal Death ◽

Epileptic Seizures ◽

Death Process ◽

Cancer Drug ◽

Neuroprotective Effects ◽

Anti Cancer ◽

Lapatinib Treatment

Epilepsy is a complex neurological disorder characterized by recurrent and unprovoked seizures. Neuronal death process is implicated in the development of repetitive epileptic seizures. Therefore, cell death can be harnessed for ceasing seizures and epileptogenesis. Oxidative stress is regarded as a contributing factor of neuronal death activation and there is compelling evidence supporting antioxidants hold promise in abrogating seizure-related cell modality. Lapatinib, a well-known anti-cancer drug, has been traditionally reported to exert anti-tumor effect via modulating oxidative stress and a recent work illustrates the improvement of encephalomyelitis in rodent models after lapatinib treatment. However, whether lapatinib is beneficial for inhibiting neuronal death and epileptic seizure remains unknown. Here, we found that lapatinib remarkably prevented kainic acid (KA)-epileptic seizures in mice and ferroptosis, a newly defined cell death which is associated with oxidative stress, was involved in the neuroprotection of lapatinib. In the ferroptotic cell death model, lapatinib exerted neuroprotection via restoring glutathione peroxidase 4 (GPX4). Treatment with GPX4 inhibitor ras-selective lethal small molecule 3 (RSL3) abrogated its anti-ferroptotic potential. In a mouse model of KA-triggered seizure, it was also validated that lapatinib blocked GPX4-dependent ferroptosis. It is concluded that lapatinib has neuroprotective potential against epileptic seizures via suppressing GPX4-mediated ferroptosis.

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The Program Cell Death (Apoptosis) and the Therapy of Cancer

10.5772/intechopen.97289 ◽

2021 ◽

Author(s):

Hilal Kalkan

Keyword(s):

Drug Resistance ◽

Cell Death ◽

Programmed Cell Death ◽

Mitochondrial Pathway ◽

Type I ◽

Incurable Cancer ◽

Cell Death Pathway ◽

Anti Cancer ◽

Apoptotic Proteins ◽

Cell Death Mechanisms

Apoptosis plays many vital roles in maintaining organ homeostasis and represents type I programmed cell death. Programmed cell death happens when the DNA damage is irremediable and has two important pathways, the intrinsic death pathway also known as the mitochondrial pathway, and the extrinsic programmed cell death pathway. Any defects in the regulation of these crucial pathways have been associated with many disorders, most importantly cancer. Therefore, understanding the molecular basis of apoptosis is essential for the treatment of incurable cancer. To date, several anti-cancer drugs have been developed by targeting anti-apoptotic proteins, which are upregulated in many cancers. Nonetheless, a disease progression often time warranted due to the deregulation of several anti or pro-apoptotic proteins which also contribute to drug resistance. Hence, it is important to understand the maintenance and counteraction of apoptosis and improve successful new pharmacological applications of cell death mechanisms for future therapies. This chapter discusses the mechanism of apoptosis and emerging principles of drug resistance in cancer.

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An Aptamer Bio-barCode (ABC) assay using SPR, RNase H, and probes with RNA and gold-nanorods for anti-cancer drug screening

The Analyst ◽

10.1039/c7an01026e ◽

2017 ◽

Vol 142 (19) ◽

pp. 3579-3587 ◽

Cited By ~ 13

Author(s):

Jacky Fong-Chuen Loo ◽

Chengbin Yang ◽

Hing Lun Tsang ◽

Pui Man Lau ◽

Ken-Tye Yong ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Gold Nanorods ◽

Drug Screening ◽

Rnase H ◽

Cancer Drug ◽

Next Generation ◽

Anti Cancer ◽

A Cell

We have developed a next generation aptamer-based bio-barcode (ABC) assay to detect cytochrome-c (Cyto-c), a cell death marker released from cancer cells, for anti-cancer drug screening.

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