Shlepova O V, Bychkov M L, Shipunova V O, Shramova E I, Shulepko M A, Gornostaeva T Y, Kiseleva E A, Kukushkin I D, Kazakov V A, Tukhovskaya E A, Dyachenko I A, Murashev A N, Shenkarev Z O, Deyev S M, Kirpichnikov M P, Lyukmanova E N
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russian Federation.
Moscow Center for Advanced Studies, Moscow, 123592 Russian Federation.
Acta Naturae. 2025 Jan-Mar;17(1):87-96. doi: 10.32607/actanaturae.27526.
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 . 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.
鳞状细胞癌（SCC）等皮肤癌是最具侵袭性的肿瘤类型之一。它们具有高生长率、高转移率，且常出现化疗耐药性。吸烟是SCC进展的风险因素之一，而α7烟碱型乙酰胆碱受体（α7-nAChR）是SCC治疗的一个有前景的靶点。人类分泌蛋白SLURP-1是上皮细胞稳态的自分泌/旁分泌调节因子，也是α7-nAChR的选择性负变构调节剂。最近，我们证明了基于重组SLURP-1的疗法在控制SCC细胞生长和转移方面具有高效性。SLURP-1的抗肿瘤作用是通过与α7-nAChR和表皮生长因子受体（EGFR）相互作用介导的。细胞毒性抗生素阿霉素已被提议用于SCC治疗；然而，由于其高毒性，其应用受到限制。在本研究中，我们研究了增加SLURP-1剂量以及将SLURP-1与低剂量阿霉素联合用于接种鳞状细胞癌A431细胞的小鼠SCC治疗的效果。增加SLURP-1剂量并未显著提高治疗效率。然而，与阿霉素联合使用进一步增强了SLURP-1的抗肿瘤活性，并显著抑制了转移。联合治疗的效果伴随着肿瘤中EGFR表达的下调。研究表明SLURP-1可直接抑制EGFR激活。联合治疗未出现毒性。我们的数据表明，低剂量的SLURP-1与化疗联合是SCC治疗中一种有前景的方法，应进一步研究。
