Isoconazole and Clemizole Hydrochloride Partially Reverse the Xeroderma Pigmentosum C Phenotype

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 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.

Clinical prognostic significance of xeroderma pigmentosum group C and IFN‑γ in non‑small cell lung cancer

“…Xeroderma pigmentosum group C (XPC) is a DNA damage recognition factor and a promoter of nucleotide excision repair that plays an important role in maintaining DNA stability (3). XPC is a key factor in the development of a number of tumor types including lung cancer (4)(5)(6)(7). Our previous study revealed that a reduction in XPC expression can markedly promote the stem cell properties of lung cancer cells and increase the proliferation and migration of lung cancer cells, and a low XPC expression in patients with lung cancer is associated with poor prognosis (8).…”

Molecular Effects of Mutations in Human Genetic Diseases

“…The eight papers published in this SI described case studies that may provide a useful framework for understanding the general molecular defects underlying a broad and diverse spectrum of human diseases. These included multifactorial or polygenic disorders, such as lung cancer (OMIM*612052) and osteoporosis (OMIM*166710) [ 1 , 2 ], or monogenic disorders, such as Long QT Syndrome 1 (LQT; OMIM*192500), Hyaline fibromatosis syndrome (OMIM*228600), Dystrophic epidermolysis bullosa (RDEB; OMIM*226600), Xeroderma Pigmentosum C Phenotype (XP-C; OMIM*278720), and MTHFR deficiency (OMIM*236250) [ 3 , 4 , 5 , 6 , 7 ].…”

“…To highlight possible mechanisms of protein destabilisation due to residue change, Savojardo et al explored the structural impact of all 72 reported disease-causing variants of the MTHFR gene [ 8 ]. In other cases, as that of Kobaisi et al, the studied variant depends on the available patient-derived cells to be used as a model system for a specific disease [ 7 ].…”

“…Another example of a protein-specific test is provided by Kobaisi et al, who evaluated the expression of XPC, a DNA damage sensor protein, and measured the photosensitivity, and the ability to repair UltraViolet B radiation (UVB)-induced lesions of XP-C cells immortalised from patient primary fibroblasts. In this case, the readout of the protein function were the photoproducts generated after UVB exposure and measured by LC-MS/MS in the DNA extracted from XP-C cells [ 7 ].…”

“…Furthermore, the molecular or morphological properties observed in the targeted model system can be used to systematically test an array of chemicals to rescue the observed pathological phenotype. This SI includes the work of Kobaisi et al, who performed a high-throughput screen to identify chemicals capable of ameliorate the hyper-photosensitivity and accumulation of photoproducts observed in XPC-mutated cells [ 7 ].…”