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March 8, 2025
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The m-TORC1 inhibitor Sirolimus increases the effectiveness of Photodynamic therapy in the treatment of cutaneous Squamous Cell Carcinoma, impairing NRF2 antioxidant signaling.

Publicated to:International Journal Of Biological Sciences. 20 (11): 4238-4257 - 2024-01-01 20(11), DOI: 10.7150/ijbs.94883

Authors: Nicolás-Morala J; Mascaraque-Checa M; Gallego-Rentero M; Barahona A; Abarca-Lachen E; Carrasco E; Gilaberte Y; González S; Juarranz Á

Affiliations

Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain. - Author
Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain.; Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain. - Author
Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain.; Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain.; Centro de Biología Molecular Severo Ochoa (CB - Author
Department of Medicine and Medical Specialties, Universidad Alcalá de Henares, 28805 Madrid, Spain. - Author
Dermatology service, Hospital Miguel Servet, Zaragoza (50009), Spain. - Author
Faculty of Health Sciences, Universidad San Jorge, 50830 Villanueva de Gállego, Spain. - Author
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Abstract

Squamous Cell Carcinoma (SCC) is a subtype of Non-Melanoma Skin Cancer, the most common group of malignancies worldwide. Photodynamic therapy (PDT) is a non-invasive treatment approved for specific subtypes of SCC. Some malignancies resist PDT, forming more aggressive tumors and multiple relapses. Thus, new approaches aimed at optimizing the response to PDT are needed. The mTORC1 inhibitor rapamycin, also known as Sirolimus (SRL), interferes with protein synthesis and cell metabolism. The use of SRL as an immunosuppressant is associated to lower rates of SCC in kidney-transplanted patients, which are frequently affected by this pathology. We have evaluated SRL pre-treatment efficacy to enhance the damage induced by PDT with Methyl 5-aminolevulinate in two different cutaneous SCC established cell lines (SCC13 and A431) in vitro and therapy sensitization in PDT-resistant cell lines. We tested for the first time the SRL + PDT combination in a SKH-1 mouse model of photocarcinogenesis, diminishing the frequency of lesions and restraining tumor growth. Molecular studies revealed that protoporphyrin IX and reactive oxygen species production induced by PDT were promoted by SRL pre-treatment. Lastly, SRL modifies the expression and intracellular location of NRF2, interfering with the downstream antioxidant response modulated by NQO1 and HO-1. In conclusion, we propose SRL as a potential adjuvant to enhance PDT efficacy for SCC treatment.

Keywords

Aminolevulinic acidAnimalsAntioxidant responseAntioxidantsCarcinoma, squamous cellCell line, tumorCutaneous squamous cell carcinomaFemaleHumansMechanistic target of rapamycin complex 1MiceNf-e2-related factor 2Nfe2l2 protein, humanPhotochemotherapyPhotodynamic therapyRapamycinReactive oxygen speciesSignal transductionSirolimusSkin neoplasmsTumor resistance

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal International Journal Of Biological Sciences due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 26/319, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biochemistry & Molecular Biology. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-10-21:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 4 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

    • The work has been submitted to a journal whose editorial policy allows open Open Access publication.