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Article ; Online: Role of protein S-Glutathionylation in cancer progression and development of resistance to anti-cancer drugs.

Pal, Debojyoti / Rai, Archita / Checker, Rahul / Patwardhan, R S / Singh, Babita / Sharma, Deepak / Sandur, Santosh K

2021 Volume 704, Page(s) 108890

Abstract: ... by a process called S-glutathionylation. S-Glutathionylation not only protects the labile cysteine residues ... on their dependence on S-glutathionylation of specific redox-sensitive proteins involved in a wide range of processes ... recycling. We also provide insights into the role of S-glutathionylation in the development of resistance ...

Abstract	The survival, functioning and proliferation of mammalian cells are highly dependent on the cellular response and adaptation to changes in their redox environment. Cancer cells often live in an altered redox environment due to aberrant neo-vasculature, metabolic reprogramming and dysregulated proliferation. Thus, redox adaptations are critical for their survival. Glutathione plays an essential role in maintaining redox homeostasis inside the cells by binding to redox-sensitive cysteine residues in proteins by a process called S-glutathionylation. S-Glutathionylation not only protects the labile cysteine residues from oxidation, but also serves as a sensor of redox status, and acts as a signal for stimulation of downstream processes and adaptive responses to ensure redox equilibrium. The present review aims to provide an updated overview of the role of the unique redox adaptations during carcinogenesis and cancer progression, focusing on their dependence on S-glutathionylation of specific redox-sensitive proteins involved in a wide range of processes including signalling, transcription, structural maintenance, mitochondrial functions, apoptosis and protein recycling. We also provide insights into the role of S-glutathionylation in the development of resistance to chemotherapy. Finally, we provide a strong rationale for the development of redox targeting drugs for treatment of refractory/resistant cancers.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Drug Resistance, Neoplasm ; Glutathione/metabolism ; Humans ; Neoplasm Proteins/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Oxidation-Reduction ; Protein Processing, Post-Translational
Chemical Substances	Antineoplastic Agents ; Neoplasm Proteins ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2021-04-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2021.108890
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Article: Role of protein S-Glutathionylation in cancer progression and development of resistance to anti-cancer drugs

Pal, Debojyoti / Rai, Archita / Checker, Rahul / Patwardhan, R.S / Singh, Babita / Sharma, Deepak / Sandur, Santosh K

Archives of biochemistry and biophysics. 2021 June 15, v. 704

2021

Abstract	The survival, functioning and proliferation of mammalian cells are highly dependent on the cellular response and adaptation to changes in their redox environment. Cancer cells often live in an altered redox environment due to aberrant neo-vasculature, metabolic reprogramming and dysregulated proliferation. Thus, redox adaptations are critical for their survival. Glutathione plays an essential role in maintaining redox homeostasis inside the cells by binding to redox-sensitive cysteine residues in proteins by a process called S-glutathionylation. S-Glutathionylation not only protects the labile cysteine residues from oxidation, but also serves as a sensor of redox status, and acts as a signal for stimulation of downstream processes and adaptive responses to ensure redox equilibrium. The present review aims to provide an updated overview of the role of the unique redox adaptations during carcinogenesis and cancer progression, focusing on their dependence on S-glutathionylation of specific redox-sensitive proteins involved in a wide range of processes including signalling, transcription, structural maintenance, mitochondrial functions, apoptosis and protein recycling. We also provide insights into the role of S-glutathionylation in the development of resistance to chemotherapy. Finally, we provide a strong rationale for the development of redox targeting drugs for treatment of refractory/resistant cancers.
Keywords	apoptosis ; biophysics ; carcinogenesis ; cysteine ; drug therapy ; glutathione ; homeostasis ; mammals ; mitochondria ; neoplasm progression ; oxidation
Language	English
Dates of publication	2021-0615
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2021.108890
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Article ; Online: Future Perspectives of Wharton's Jelly Mesenchymal Stem Cells and their Soluble Factors in Radioprotection.

Kumar Maurya, Dharmendra / Kumar Sandur, Santosh

Current stem cell research & therapy

2023

Abstract: Acute radiation syndrome (ARS) is also known as triple syndrome, which develops after whole-body radiation exposure. During unforeseen exposures, these syndromes are set in depending on the dose of radiation. Cell-based therapy, especially using stem ... ...

Abstract	Acute radiation syndrome (ARS) is also known as triple syndrome, which develops after whole-body radiation exposure. During unforeseen exposures, these syndromes are set in depending on the dose of radiation. Cell-based therapy, especially using stem cells and their soluble factors, is gaining wide attention in the field of regenerative medicine to treat various diseases, including degenerative diseases. Stem cells attract prime attention because of their profound inherent tissue repair capability and regeneration potential. Further, stem cell therapy can be one of the promising strategies for the amelioration of ARS because of its ability to lodge in damaged tissue and release regenerative cytokines by sensing the local injury. In this regard, human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSCs) have gained substantial attention for their applications in the treatment of various human diseases due to several advantages offered by them. This article is intended to provide future perspective on the use of WJ-MSCs for the management of accidental radiation injury in pre-clinical models, and finally, their utility in regeneration of damaged tissues and organs.
Language	English
Publishing date	2023-01-19
Publishing country	United Arab Emirates
Document type	Journal Article
ZDB-ID	2251937-3
ISSN	2212-3946 ; 1574-888X
ISSN (online)	2212-3946
ISSN	1574-888X
DOI	10.2174/1574888X18666230119103905
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Article ; Online: Hypoxia induces dichotomous and reversible attenuation of T cell responses through reactive oxygen species-dependent phenotype redistribution and delay in lymphoblast proliferation.

Maurya, Dharmendra Kumar / Sharma, Deepak / Sandur, Santosh Kumar

Free radical research

2023 Volume 57, Issue 1, Page(s) 1–13

Abstract: ... Cell cycle analysis revealed maximum levels of cytosolic and mitochondrial ROS in dividing T cells (in S, G2 ...

Abstract	As T cells transit between blood, lymphoid organs, and peripheral tissues, they experience varied levels of oxygen/hypoxia in inflamed tissues, skin, intestinal lining, and secondary lymphoid organs. Critical illness among COVID-19 patients is also associated with transient hypoxia and attenuation of T cell responses. Hypoxia is the fulcrum of altered metabolism, impaired functions, and cessation of growth of a subset of T cells. However, the restoration of normal T cell functions following transient hypoxia and kinetics of their phenotype-redistribution is not completely understood. Here, we sought to understand kinetics and reversibility of dichotomous T cell responses under sustained and transient hypoxia. We found that a subset of activated T cells accumulated as lymphoblasts under hypoxia. Further, T cells showed the normal expression of activation markers CD25 and CD69 and inflammatory cytokine secretion but a subset exhibited delayed cell proliferation under hypoxia. Increased levels of reactive oxygen species (ROS) in cytosol and mitochondria were seen during dichotomous and reversible attenuation of T cell response under hypoxia. Cell cycle analysis revealed maximum levels of cytosolic and mitochondrial ROS in dividing T cells (in S, G2, or M phase). Hypoxic T cells also showed specific attenuation of activation induced memory phenotype conversion without affecting naïve and activated T cells. Hypoxia-related attenuation of T cell proliferation was also found to be reversible in an allogeneic leukocyte specific mixed lymphocyte reaction assay. In summary, our results show that hypoxia induces a reversible delay in proliferation of a subset of T cells which is associated with obliteration of memory phenotype and specific increase in cytosolic/mitochondrial ROS levels in actively dividing subpopulation. Thus, the transient reoxygenation of hypoxic patients may restore normal T cell responses.
MeSH term(s)	Humans ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/metabolism ; Cell Hypoxia ; COVID-19 ; Hypoxia/metabolism ; Oxygen/metabolism ; Cell Proliferation ; Phenotype
Chemical Substances	Reactive Oxygen Species ; Oxygen (S88TT14065)
Language	English
Publishing date	2023-03-22
Publishing country	England
Document type	Journal Article
ZDB-ID	1194130-3
ISSN	1029-2470 ; 1071-5762
ISSN (online)	1029-2470
ISSN	1071-5762
DOI	10.1080/10715762.2023.2178918
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Article: Txnrd1 as a prognosticator for recurrence, metastasis and response to neoadjuvant chemotherapy and radiotherapy in breast cancer patients.

Patwardhan, Raghavendra S / Rai, Archita / Sharma, Deepak / Sandur, Santosh K / Patwardhan, Sejal

Heliyon

2024 Volume 10, Issue 6, Page(s) e27011

Abstract: Thioredoxin reductase 1 (Txnrd1) is known to have prognostic significance in a subset of breast cancer patients. Despite the pivotal role of Txnrd1 in regulating several cellular and physiological processes in cancer progression and metastasis, its ... ...

Abstract	Thioredoxin reductase 1 (Txnrd1) is known to have prognostic significance in a subset of breast cancer patients. Despite the pivotal role of Txnrd1 in regulating several cellular and physiological processes in cancer progression and metastasis, its clinical significance is largely unrecognized. Here, we undertook a retrospective comprehensive meta-analysis of 13,322 breast cancer patients from 43 independent cohorts to assess prognostic and predictive roles of Txnrd1. We observed that Txnrd1 has a positive correlation with tumor grade and size and it is over-expressed in higher-grade and larger tumors. Further, hormone receptor-negative and HER2-positive tumors exhibit elevated Txnrd1 gene expression. Patients with elevated Txnrd1 expression exhibit significant hazards for shorter disease-specific and overall survival. While Txnrd1 has a positive correlation with tumor recurrence and metastasis, it has a negative correlation with time to recurrence and metastasis. Txnrd1
Language	English
Publishing date	2024-02-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2024.e27011
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Article ; Online: Picosecond laser-induced hybrid groove structures on Ti-6Al-4V bio-alloy to accelerate osseointegration.

Kedia, S / Checker, R / Sandur, S K / Nilaya, J P

Journal of biomedical materials research. Part B, Applied biomaterials

2023 Volume 111, Issue 10, Page(s) 1775–1784

Abstract: Regulating cell growth, extracellular matrix deposition and mineralization of artificial implants are some important parameters that decide the longevity of implants in the body. Picosecond laser-induced hybrid groove structures have been shown to ... ...

Abstract	Regulating cell growth, extracellular matrix deposition and mineralization of artificial implants are some important parameters that decide the longevity of implants in the body. Picosecond laser-induced hybrid groove structures have been shown to improve these properties of the Ti-6Al-4V bio-alloy. Two hybrid structures containing groove patterns with periodic and non-periodic substructures therein were generated on Ti-6Al-4V by varying the extent of laser pulse overlapping on sample surface. Laser-induced alteration in surface topography, chemical composition and wettability of Ti-6Al-4V resulted in 3-fold increase in the rate of hydroxyapatite growth, 2.5-fold increment in protein adsorption and 2-fold enhancement in cell adhesion in comparison to pristine sample. While the periodic substructure was found to guide cell growth, the nonperiodic sub structure offered homogenous growth leading to higher overall cell density on the substrate surface.
MeSH term(s)	Osseointegration ; Lasers ; Titanium/chemistry ; Alloys ; Surface Properties
Chemical Substances	titanium alloy (TiAl6V4) (12743-70-3) ; Titanium (D1JT611TNE) ; Alloys
Language	English
Publishing date	2023-06-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2099992-6
ISSN	1552-4981 ; 1552-4973 ; 0021-9304
ISSN (online)	1552-4981
ISSN	1552-4973 ; 0021-9304
DOI	10.1002/jbm.b.35284
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Article: Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer.

Patwardhan, Raghavendra S / Sharma, Deepak / Sandur, Santosh K

Translational oncology

2022 Volume 17, Page(s) 101341

Abstract: Novel agents are required to increase the radiosensitivity of cancer and improve the outcome of radiotherapy. Thioredoxin (Trx) and thioredoxin reductase (TrxR) reduce the oxidized cysteine thiols in several proteins, which regulate cellular redox, ... ...

Abstract	Novel agents are required to increase the radiosensitivity of cancer and improve the outcome of radiotherapy. Thioredoxin (Trx) and thioredoxin reductase (TrxR) reduce the oxidized cysteine thiols in several proteins, which regulate cellular redox, survival, proliferation, DNA synthesis, transcription factor activity and apoptosis. TrxR is essential for maintaining a conducive redox state for tumor growth, survival and resistance to therapy. Therefore, it is an appealing pharmacological target for the radiosensitization of tumors. Ionizing radiation (IR) is known to cause cytotoxicity through ROS, oxidative stress and DNA damage. Inhibition of thioredoxin system augments IR induced oxidative stress and potentiates cytotoxic effects. However, TrxR also regulates several critical cellular processes in normal cells. Here, we highlight the pre-clinical research and pharmacological studies to surmise possible utility of different TrxR inhibitors for radiosensitization. This review provides a succinct perspective on the role of TrxR inhibitors during the radiotherapy of cancer.
Language	English
Publishing date	2022-01-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2443840-6
ISSN	1936-5233
ISSN	1936-5233
DOI	10.1016/j.tranon.2022.101341
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Article ; Online: Clobetasol propionate, a Nrf-2 inhibitor, sensitizes human lung cancer cells to radiation-induced killing via mitochondrial ROS-dependent ferroptosis.

Rai, Archita / Patwardhan, Raghavendra S / Jayakumar, Sundarraj / Pachpatil, Pradnya / Das, Dhruv / Panigrahi, Girish Ch / Gota, Vikram / Patwardhan, Sejal / Sandur, Santosh K

Acta pharmacologica Sinica

2024

Abstract: Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was ...

Abstract	Combining radiotherapy with Nrf-2 inhibitor holds promise as a potential therapeutic strategy for radioresistant lung cancer. Here, the radiosensitizing efficacy of a synthetic glucocorticoid clobetasol propionate (CP) in A549 human lung cancer cells was evaluated. CP exhibited potent radiosensitization in lung cancer cells via inhibition of Nrf-2 pathway, leading to elevation of oxidative stress. Transcriptomic studies revealed significant modulation of pathways related to ferroptosis, fatty acid and glutathione metabolism. Consistent with these findings, CP treatment followed by radiation exposure showed characteristic features of ferroptosis in terms of mitochondrial swelling, rupture and loss of cristae. Ferroptosis is a form of regulated cell death triggered by iron-dependent ROS accumulation and lipid peroxidation. In combination with radiation, CP showed enhanced iron release, mitochondrial ROS, and lipid peroxidation, indicating ferroptosis induction. Further, iron chelation, inhibition of lipid peroxidation or scavenging mitochondrial ROS prevented CP-mediated radiosensitization. Nrf-2 negatively regulates ferroptosis through upregulation of antioxidant defense and iron homeostasis. Interestingly, Nrf-2 overexpressing A549 cells were refractory to CP-mediated ferroptosis induction and radiosensitization. Thus, this study identified anti-psoriatic drug clobetasol propionate can be repurposed as a promising radiosensitizer for Keap-1 mutant lung cancers.
Language	English
Publishing date	2024-03-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/s41401-024-01233-8
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Article ; Online: Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis.

Checker, Rahul / Bhilwade, H N / Nandha, Shivani R / Patwardhan, Raghavendra S / Sharma, Deepak / Sandur, Santosh K

Toxicology and applied pharmacology

2023 Volume 461, Page(s) 116389

Abstract: Increasing use of ionizing radiation (IR) in medicine, industry, agriculture and research ensues potential health hazards if not used properly or contained effectively. However, radioprotectors which are effective in clinical and/or accidental radiation ... ...

Abstract	Increasing use of ionizing radiation (IR) in medicine, industry, agriculture and research ensues potential health hazards if not used properly or contained effectively. However, radioprotectors which are effective in clinical and/or accidental radiation exposures are still elusive. In this direction, we have explored the radioprotective potential of Withaferin A, a plant withanolide, which was recently shown to be safe and well tolerated in cancer patients in a clinical trial and is also known to be a radio-sensitizer in cancer cells. Our results show that, Withaferin A (WA) protected only normal lymphocytes, but not cancer cells, against IR-induced apoptosis and offered radioprotection even when added post-radiation exposure. WA treatment led to significant inhibition of IR-induced caspase-3 activation and decreased IR-induced DNA damage to lymphocytes and bone-marrow cells. WA reduced intracellular ROS and GSH levels and only thiol based anti-oxidants could abrogate the radio-protective effects of WA, indicating a crucial role of cellular/protein thiols in its biological activity. The inability of WA-glutathione adduct to offer radioprotection further underscored the role of cellular thiols. WA induced pro-survival transcription factor, Nrf-2, and expression of cytoprotective genes HO-1, catalase, SOD, peroxiredoxin-2 via ERK. Further, WA administration could rescue mice against radiation induced mortality, DNA damage, increase in micro-nucleated polychromatic erythrocytes (mn-PCEs) and increased ratio of polychromatic erythrocytes (PCEs) to Normochromatic Erythrocytes (NCEs) in bone-marrow, demonstrating its potent in vivo the radio-protective efficacy. In conclusion, WA selectively protects normal cells against IR-induced apoptosis via activation of cytoprotective Nrf-2 pathway.
MeSH term(s)	Mice ; Animals ; Withanolides/pharmacology ; Lymphocytes ; Radiation, Ionizing ; Apoptosis ; DNA Damage ; Glutathione/metabolism ; Sulfhydryl Compounds
Chemical Substances	withaferin A (L6DO3QW4K5) ; Withanolides ; Glutathione (GAN16C9B8O) ; Sulfhydryl Compounds
Language	English
Publishing date	2023-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	204477-8
ISSN	1096-0333 ; 0041-008X
ISSN (online)	1096-0333
ISSN	0041-008X
DOI	10.1016/j.taap.2023.116389
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Article ; Online: Role and management of oxidative stress in human disease.

Checker, Rahul / Sharma, Deepak / Sandur, Santosh K / Toyokuni, Shinya

Free radical research

2021 Volume 55, Issue 8, Page(s) 755–757

MeSH term(s)	Disease/genetics ; Humans ; Oxidative Stress/genetics
Language	English
Publishing date	2021-10-16
Publishing country	England
Document type	Editorial
ZDB-ID	1194130-3
ISSN	1029-2470 ; 1071-5762
ISSN (online)	1029-2470
ISSN	1071-5762
DOI	10.1080/10715762.2021.1991083
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