O V Shlepova, M L Bychkov, V O Shipunova, E I Shramova, M A Shulepko, T Y Gornostaeva, E A Kiseleva, I D Kukushkin, V A Kazakov, E A Tukhovskaya, I A Dyachenko, A N Murashev, Z O Shenkarev, S M Deyev, M P Kirpichnikov, E N Lyukmanova
{"title":"Combination with a Low Dose of Doxorubicin Further Boosts the Antitumor Effect of SLURP-1 In Vivo and Associates with EGFR Down-Regulation.","authors":"O V Shlepova, M L Bychkov, V O Shipunova, E I Shramova, M A Shulepko, T Y Gornostaeva, E A Kiseleva, I D Kukushkin, V A Kazakov, E A Tukhovskaya, I A Dyachenko, A N Murashev, Z O Shenkarev, S M Deyev, M P Kirpichnikov, E N Lyukmanova","doi":"10.32607/actanaturae.27526","DOIUrl":null,"url":null,"abstract":"<p><p>Skin cancers such as squamous cell carcinoma (SCC) are among the most aggressive types of tumors. They come with a high rate of growth, metastasis, and frequently occurring chemoresistance. Smoking is one of the risk factors for SCC progression, and the α7 nicotinic acetylcholine receptor (α7-nAChR) is a promising target for SCC therapy. Human secreted protein SLURP-1 is an auto/paracrine regulator of epithelial homeostasis and a selective negative allosteric modulator of α7-nAChR. Recently, we demonstrated the high efficiency of the therapy based on the recombinant SLURP-1 in controlling SCC cell growth and metastasis <i>in vivo</i>. The anti-tumor effect of SLURP-1 was mediated through interaction with both α7-nAChR and the epidermal growth factor receptor (EGFR). Cytotoxic antibiotic doxorubicin has been proposed for the SCC therapy; however, its use is limited due to the high toxicity. In this study we investigated the use of an enhanced SLURP-1 dose and of a combination of SLURP-1 with low-dozen doxorubicin for SCC treatment of mice xenografted with squamous cell carcinoma A431 cells. An increased SLURP-1 dose didn't significantly enhance the efficiency of the therapy. However, the combination with doxorubicin further enhanced the anti- tumor activity of SLURP-1 and dramatically suppressed metastasis. The effect from the combined therapy was accompanied by down-regulation of EGFR expression in tumors. Direct inhibition of EGFR activation by SLURP-1 was shown. No toxicity of the combined therapy was encountered. Our data indicate that the combination of SLURP-1 with chemotherapy in lower doses is a promising approach in SCC treatment and should be further studied.</p>","PeriodicalId":6989,"journal":{"name":"Acta Naturae","volume":"17 1","pages":"87-96"},"PeriodicalIF":2.0000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011185/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Naturae","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.32607/actanaturae.27526","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Skin cancers such as squamous cell carcinoma (SCC) are among the most aggressive types of tumors. They come with a high rate of growth, metastasis, and frequently occurring chemoresistance. Smoking is one of the risk factors for SCC progression, and the α7 nicotinic acetylcholine receptor (α7-nAChR) is a promising target for SCC therapy. Human secreted protein SLURP-1 is an auto/paracrine regulator of epithelial homeostasis and a selective negative allosteric modulator of α7-nAChR. Recently, we demonstrated the high efficiency of the therapy based on the recombinant SLURP-1 in controlling SCC cell growth and metastasis in vivo. The anti-tumor effect of SLURP-1 was mediated through interaction with both α7-nAChR and the epidermal growth factor receptor (EGFR). Cytotoxic antibiotic doxorubicin has been proposed for the SCC therapy; however, its use is limited due to the high toxicity. In this study we investigated the use of an enhanced SLURP-1 dose and of a combination of SLURP-1 with low-dozen doxorubicin for SCC treatment of mice xenografted with squamous cell carcinoma A431 cells. An increased SLURP-1 dose didn't significantly enhance the efficiency of the therapy. However, the combination with doxorubicin further enhanced the anti- tumor activity of SLURP-1 and dramatically suppressed metastasis. The effect from the combined therapy was accompanied by down-regulation of EGFR expression in tumors. Direct inhibition of EGFR activation by SLURP-1 was shown. No toxicity of the combined therapy was encountered. Our data indicate that the combination of SLURP-1 with chemotherapy in lower doses is a promising approach in SCC treatment and should be further studied.
期刊介绍:
Acta Naturae is an international journal on life sciences based in Moscow, Russia.
Our goal is to present scientific work and discovery in molecular biology, biochemistry, biomedical disciplines and biotechnology. These fields represent the most important priorities for the research and engineering development both in Russia and worldwide. Acta Naturae is also a periodical for those who are curious in various aspects of biotechnological business, innovations in pharmaceutical areas, intellectual property protection and social consequences of scientific progress. The journal publishes analytical industrial surveys focused on the development of different spheres of modern life science and technology.
Being a radically new and totally unique journal in Russia, Acta Naturae is useful to both representatives of fundamental research and experts in applied sciences.