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Selective activation of drugs by redox processes

View all copies of this ISBN edition:. Buy New Learn more about this copy. Other Popular Editions of the Same Title. Induction of apoptosis or necrosis is linked with lipid raft-mediated downstream ROS generation [ 30 , 31 ]. ROS promote apoptosis via JNK activation, inducing either intrinsic or extrinsic apoptotic signalling [ 35 ]. Saxena et al.

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This suppression of the inhibition is mediated by Trx2 results in ASK1phosphorylation and induction of the mitochondrial pathway for apoptosis with caspase-3 cleavage and cytochrome c release [ 38 ]. The major target for ROS inside the mitochondria is the permeability transition pore mPTP in which the oxidative modification of its proteins has significant influence on the anion fluxes within the mitochondria [ 39 ]. The above phenomenon is termed mitochondrial permeability transition MPT , which results in mitochondrial membrane potential dissipation and consequent osmotic swelling of the matrix of the mitochondria due to fluid influx [ 40 ].

The early phase of the mitochondrial swelling involves water movement from inter-cristae spaces into the mitochondrial matrix.

Pharmacokinetics 1 - Introduction

This causes cytochrome c to be released with consequent activation of the downstream effector caspases by Apafpro-caspase 9-apoptosome complex. The antioxidant systems are either enzymatic or non-enzymatic. A study has demonstrated that lack of MnSOD in mice generated excessive oxidative stress causing their mortality [ 46 ]. Another study also revealed that mice with a deficiency of CuZnSOD developed hepatocellular carcinoma due to sustained oxidative damage [ 47 ]. GPX is a selenium-dependent antioxidant enzyme, which regulates hydrogen and lipid peroxide levels. An increased risk of bladder cancer, lung cancer and breast cancer has been associated with the substitution of proline-leucine at codon in human GPX [ 52 , 53 , 54 , 55 ].

The protective function of thioredoxins Trxs in cells against oxidative stress is via the reaction between their active site known as 2-cysteine and ROS resulting in reduction of oxidised proteins. Trxs also function as hydrogen donors to thioredoxin-dependent peroxide reductases.

Trx possesses a Cys-Gly-Pro-Cys active site, which is essential for redox regulatory functions of Trx. Trx, when combined with Trx reductase and NADPH, forms a redox-sensitive machinery, which controls the levels of oxidised cysteine on proteins. The antioxidant properties of Trx can be attributed to the reduction of the oxidised form of Trx peroxidase by Trx, while the reduced peroxidase scavenges H 2 O 2 [ 45 ].

The two isoforms of Trx are Trx1 expressed in the cytoplasm and the nucleus and Trx2 expressed in the mitochondria , which are very crucial for cell survival [ 56 ]. Trx1 has been linked to breast tumours, colon cancer, cervical cancer, gastric cancer, lung cancer, liver cancer and melanoma and carcinomas of the pancreas [ 58 , 59 , 60 , 61 , 62 ].


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GSH is a thiol protein consisting of cysteine, glutamine and glycine, which functions as an important antioxidant in detoxification of metabolic processes [ 63 ]. Elevated levels of GSH in the cancerous patient tissue are reinforced by improved accessibility to the biosynthetic elements of GSH, such as glutamate, cysteine and glycine [ 64 , 65 ]. Glutamate cysteine ligase modifier subunit GCLM is also upregulated in many types of human cancer but also requisite for effective GSH synthesis [ 67 ]. Maintenance and elevation of GSH levels in cells are critical for the initiation and proliferation of tumours [ 67 , 68 ].

Also, elevated levels of GSH increase antioxidant activities against numerous cancer cells, thereby enhancing the resistance of the cancer cells against oxidative stress [ 69 ]. Mechanism of ROS formation and disposal. Enzymatically or non-enzymatically generated superoxide reacts with other radicals. The generated superoxide and H2O2 form hydroxyl radicals and singlet oxygen. Thiol, a component of cysteine found in Prx, is oxidatively converted into Cys-sulfenic acid by Prxox and subsequently reduced by thioredoxin Trxred.

Cys-SOH formed functions to regulate protein activities by absorbing the oxidative insults leading to the deflection of injurious oxidative impairment [24]. Prxs are made up of six isoenzyme families capable of reducing H 2 O 2 and alkyl hydroperoxides to their resultant H 2 O or alcohol. Prxs are essential antioxidants that mediate the balancing mechanism of cellular H 2 O 2 production, which is necessary for signalling and cell metabolism [ 70 ].

Nrf2 upregulates Prxs in oxidative stress circumstances [ 71 ]. PRDX1 plays the role of tumour suppressor in the development of breast cancer by interacting with oncogene c-Myc suppressing its transcriptional action [ 72 , 73 ].

Redox Reactions Catalyzed by Isolated Enzymes | Chemical Reviews

NADPH oxidase is hetero-proteins, which consist of seven isoforms. This development assists cells to retain redox balance in the mitochondria averting the oxidative trauma received as a result of the detachment from the extracellular matrix [ 75 ]. ATM-regulated tumour suppressor works by interfering with KEAP1-facilitated NRF2 ubiquitination, thereby activating and stabilising the major regulators of antioxidants [ 77 ]. ROS levels are inherently elevated in cancer cells owing to mitochondrial defective oxidative metabolism [ 84 ].

Upregulated oxidative signals are implicated in the development and advancement of different cancer types [ 85 ]. Raised levels of ROS contribute to the initiation of cancer, transformation to malignancy and therapy resistance. For instance, silent information regulators of gene transcription-3 sirtuin-3 are crucial in ROS regulation and effective flow of electrons via ETC. Failure in sirtuin-3 activities elevates intracellular levels of ROS, thereby inducing instability to the DNA of the mitochondria [ 86 ].

Sirtuins are involved in the catalysis of exclusive reactions that lead to the formation of deacetylated substrate, acetyl ADP-ribose AADPR and nicotinamide [ 87 ]. Also, SIRT1 interrupts apoptosis, rescuing vulnerable cells after repetitive oxidative stress exposure [ 60 ]. Christensen, David J. Chaplin, Jens Overgaard.


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Stratford, G. Adams, J. Bremner, S.

Selective Activation of Drugs by Redox Processes

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Rami, Peter Wardman. Toxicity of Metal Complexes with Radiosensitizing Properties. Edwards, J. Tocher, L. Dale, D. Widdick, N. Whitmore, A. Dulhanty, A. Varghese, S. Busutti, A.