scholarly journals Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

2021 ◽  
Author(s):  
Farah Kobaisi ◽  
Eric Sulpice ◽  
Caroline Barette ◽  
Nour Fayyad ◽  
Marie-Odile Fauvarque ◽  
...  
Keyword(s):  
Dna Damage ◽  
Skin Cancer ◽  
Synergistic Effect ◽  
Xeroderma Pigmentosum ◽  
Protein C ◽  
Molecular Mechanisms ◽  
Ultra Violet ◽  
Uv Exposure ◽  
Proliferative Capacity ◽  
Cancer Initiation

Abstract Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate DNA damage leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥ 25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6 − 4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post-treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals.

scholarly journals Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

2021 ◽  
Vol 22 (15) ◽  
pp. 8156
Author(s):  
Farah Kobaisi ◽  
Eric Sulpice ◽  
Caroline Barette ◽  
Nour Fayyad ◽  
Marie-Odile Fauvarque ◽  
...  
Keyword(s):  
Dna Damage ◽  
Skin Cancer ◽  
Xeroderma Pigmentosum ◽  
Protein C ◽  
Molecular Mechanisms ◽  
Ultra Violet ◽  
Uv Exposure ◽  
Proliferative Capacity ◽  
Pyrimidine Dimers ◽  
Cancer Initiation

Xeroderma Pigmentosum protein C (XPC) is involved in recognition and repair of bulky DNA damage such as lesions induced by Ultra Violet (UV) radiation. XPC-mutated cells are, therefore, photosensitive and accumulate UVB-induced pyrimidine dimers leading to increased cancer incidence. Here, we performed a high-throughput screen to identify chemicals capable of normalizing the XP-C phenotype (hyper-photosensitivity and accumulation of photoproducts). Fibroblasts from XP-C patients were treated with a library of approved chemical drugs. Out of 1280 tested chemicals, 16 showed ≥25% photo-resistance with RZscore above 2.6 and two drugs were able to favor repair of 6-4 pyrimidine pyrimidone photoproducts (6-4PP). Among these two compounds, Isoconazole could partially inhibit apoptosis of the irradiated cells especially when cells were post-treated directly after UV irradiation while Clemizole Hydrochloride-mediated increase in viability was dependent on both pre and post treatment. No synergistic effect was recorded following combined drug treatment and the compounds exerted no effect on the proliferative capacity of the cells post UV exposure. Amelioration of XP-C phenotype is a pave way towards understanding the accelerated skin cancer initiation in XP-C patients. Further examination is required to decipher the molecular mechanisms targeted by these two chemicals.

Skin Cancer

2018 ◽  
Author(s):  
Adèle C. Green ◽  
Catherine M. Olsen ◽  
David J. Hunter
Keyword(s):  
Skin Cancer ◽  
Cell Carcinoma ◽  
Uv Radiation ◽  
Molecular Mechanisms ◽  
Sun Exposure ◽  
Uv Exposure ◽  
Skin Cancers ◽  
Cells Of Origin ◽  
Solar Ultraviolet

Skin cancer is one of the few types of cancer for which exposure to the major carcinogen, solar ultraviolet (UV) radiation, is strongly implicated on the basis of descriptive epidemiologic data alone. There are three major forms of skin cancer considered in this chapter—melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)—and each appears to have different causal relations to the pattern and total amount of sun exposure. High-intensity UV exposure and long-term UV exposure appear to be involved differentially in the various skin cancers and their subtypes. Underlying molecular mechanisms are becoming better understood, though many aspects like the cells of origin and the exact roles of intermediate lesions like actinic keratoses and nevi remain unclear. Because exposure of skin to UV radiation is modifiable, skin cancers are substantially preventable.

scholarly journals An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair

2008 ◽  
Vol 29 (5) ◽  
pp. 1276-1290 ◽  
Author(s):  
Jaan-Olle Andressoo ◽  
Geert Weeda ◽  
Jan de Wit ◽  
James R. Mitchell ◽  
Rudolf B. Beems ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Xeroderma Pigmentosum ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Cockayne Syndrome ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Neonatal Lethality ◽  
Nucleotide Excision

ABSTRACT Patients carrying mutations in the XPB helicase subunit of the basal transcription and nucleotide excision repair (NER) factor TFIIH display the combined cancer and developmental-progeroid disorder xeroderma pigmentosum/Cockayne syndrome (XPCS). Due to the dual transcription repair role of XPB and the absence of animal models, the underlying molecular mechanisms of XPBXPCS are largely uncharacterized. Here we show that severe alterations in Xpb cause embryonic lethality and that knock-in mice closely mimicking an XPCS patient-derived XPB mutation recapitulate the UV sensitivity typical for XP but fail to show overt CS features unless the DNA repair capacity is further challenged by crossings to the NER-deficient Xpa background. Interestingly, the Xpb XPCS Xpa double mutants display a remarkable interanimal variance, which points to stochastic DNA damage accumulation as an important determinant of clinical diversity in NER syndromes. Furthermore, mice carrying the Xpb XPCS mutation together with a point mutation in the second TFIIH helicase Xpd are healthy at birth but display neonatal lethality, indicating that transcription efficiency is sufficient to permit embryonal development even when both TFIIH helicases are crippled. The double-mutant cells exhibit sensitivity to oxidative stress, suggesting a role for endogenous DNA damage in the onset of XPB-associated CS.

366-OR: TCF19 Promotes Functional Beta-Cell Mass and Proliferative Capacity by Regulating DNA Damage Repair Pathways

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 366-OR
Author(s):  
GRACE H. YANG ◽  
JEE YOUNG HAN ◽  
SUKANYA LODH ◽  
JOSEPH T. BLUMER ◽  
DANIELLE FONTAINE ◽  
...  
Keyword(s):  
Dna Damage ◽  
Beta Cell ◽  
Dna Damage Repair ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Proliferative Capacity ◽  
Damage Repair ◽  
Repair Pathways

Molecular Processes Involved in Pancreatic Cancer and Therapeutics

2020 ◽  
Vol 14 ◽  
Author(s):  
Subhajit Makar ◽  
Abhrajyoti Ghosh ◽  
Divya ◽  
Shalini Shivhare ◽  
Ashok Kumar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Locally Advanced ◽  
Therapeutic Strategies ◽  
Screening Methods ◽  
Pancreatic Cancer Cells ◽  
Systemic Treatments ◽  
Cancer Initiation ◽  
Novel Therapeutic Strategies

: Despite advances in the development of cytotoxic and targeted therapies, pancreatic adenocarcinoma (PAC) remains a significant cause of cancer mortality worldwide. It is also difficult to detect it at an early stage due to numbers of factors. Most of the patients are present with locally advanced or metastatic disease, which precludes curative resection. In the absence of effective screening methods, considerable efforts have been made to identify better systemic treatments during the past decade. This review describes the recent advances in molecular mechanisms involved in pancreatic cancer initiation, progression, and metastasis. Additionally, the importance of deregulated cellular signalling pathways and various cellular proteins as potential targets for developing novel therapeutic strategies against incurable forms of pancreatic cancer is reported. The emphasis is on the critical functions associated with growth factors and their receptors viz. c-MET/HGF, CTHRC1, TGF-β, JAK-STAT, cyclooxygenase pathway, WNT, CCK, MAPK-RAS-RAF, PI3K-AKT, Notch, src, IGF-1R, CDK2NA and chromatin regulation for the sustained growth, survival, and metastasis of pancreatic cancer cells. It also includes various therapeutic strategies viz. immunotherapy, surgical therapy, radiation therapy and chemotherapy.

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