Potential mechanism of NVP‐LDE225 combined with radiotherapy for melanoma
Liu Xin1, Xiang Jiabao1, Yin Yao2, Wang Yizheng2, Chen Yifei2
1Graduate Collaborative Training Base of Academy of Military Sciences, Hengyang Medical School, University of South China, Hengyang 421001, China; 2Laboratory of Military Brain Science and Brain‐inspired Computing, Academy of Military Medical Science, Academy of Military Science, Beijing 100000, China
Abstract：Objective To explore the potential mechanism and feasibility of sonic hedgehog (SHH) signal pathway inhibitor NVP‐LDE225 combined with radiotherapy in the treatment of melanoma. Methods The Gli1 mRNA expression of the melanoma cells (Melan‐A and SK‐MEL‐2) was detected by qPCR. After treatment with NVP‐LDE225, GDC‐0449 or combined with radiation for 24 hours, the number and activity of Melan‐A and SK‐MEL‐2 were detected by cell counting and CCK‐8 kit. The survival and proliferation ratio of Melan‐A and SK‐MEL‐2 were detected by cell cloning. The changes of cell cycle of melanoma Melan‐A cells were determined by flow cytometry. The levels of the Bax and Caspase3 of Melan‐A apoptosis protein in melanoma cells were detected by Western blot. Results NVP‐LDE225, an inhibitor of Smo, decreased the mRNA expression of Gli1 in the melanoma cells in a dose‐dependent manner, inhibited the proliferation ratio of the melanoma cells, induced apoptosis, and arrested melanoma cells in G0 / G1 phase. Gamma ray irradiation after NVP‐LDE225 treatment further inhibited the SHH signal pathway, arrested the melanoma cells in G2 / M phase, and further increased the inhibitory effect on melanoma cell proliferation. Conclusions NVP‐LDE225, an inhibitor of Smo, can inhibit SHH signal pathway in melanocytes, suppress cell proliferation, and further increases the effect of inhibiting cell proliferation after combining with irradiation. It can be used as a potential drug in combination with radiotherapy in the treatment of melanoma, which is worthy of further study.
Liu Xin,Xiang Jiabao,Yin Yao et al. Potential mechanism of NVP‐LDE225 combined with radiotherapy for melanoma[J]. Chinese Journal of Radiation Oncology, 2022, 31(10): 933-938.
[1] Bobos M.Histopathologic classification and prognostic factors of melanoma: a 2021 update[J]. Ital J Dermatol Venerol, 2021,156(3):300-321. DOI: 10.23736/S2784- 8671.21.06958-3. [2] Ahmed B, Qadir MI, Ghafoor S.Malignant melanoma: skin cancer-diagnosis, prevention, and treatment[J]. Crit Rev Eukaryot Gene Expr, 2020,30(4):291-297. DOI: 10.1615/CritRevEukaryotGeneExpr.2020028454. [3] Rastrelli M, Tropea S, Rossi CR, et al.Melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification[J]. In Vivo, 2014,28(6):1005-1011. [4] Dunjic M, Lukic N, Djordjevic B, et al.GLI-1 polymorphisms of hedgehog pathway as novel risk and prognostic biomarkers in melanoma patients[J]. Melanoma Res, 2022,32(1):11-17. DOI: 10.1097/CMR.0000000000000789. [5] Volgareva GM, Mikhaylova IN, Golovina DA.[Melanoma and human papillomaviruses: is there an outlook for study?][J]. Vestn Ross Akad Med Nauk, 2016,(2):121-127. DOI: 10.15690/vramn654. [6] Zhu ZX, Sun CC, Ting Zhu Y, et al.Hedgehog signaling contributes to basic fibroblast growth factor-regulated fibroblast migration[J]. Exp Cell Res, 2017,355(2):83-94. DOI: 10.1016/j.yexcr.2017.03.054. [7] Chen H, Zuo Q, Wang Y, et al.Regulation of hedgehog signaling in chicken embryonic stem cells differentiation into male germ cells (gallus)[J]. J Cell Biochem, 2017,118(6):1379-1386. DOI: 10.1002/jcb.25796. [8] Jeng KS, Chang CF, Lin SS.Sonic Hedgehog signaling in organogenesis, tumors, and tumor microenvironments[J]. Int J Mol Sci, 2020,21(3):758.DOI: 10.3390/ijms21030758. [9] Tukachinsky H, Kuzmickas RP, Jao CY, et al.Dispatched and scube mediate the efficient secretion of the cholesterol- modified hedgehog ligand[J]. Cell Rep, 2012,2(2):308-320. DOI: 10.1016/j.celrep.2012.07.010. [10] Skoda AM, Simovic D, Karin V, et al.The role of the hedgehog signaling pathway in cancer: a comprehensive review[J]. Bosn J Basic Med Sci, 2018,18(1):8-20. DOI: 10.17305/bjbms.2018.2756. [11] Tamayo-Orrego L, Charron F. Recent advances in SHH medulloblastoma progression: tumor suppressor mechanisms and the tumor microenvironment[J]. F1000Res, 2019,8:F1000 Faculty Rev-1823. DOI: 10.12688/f1000research.20013.1. [12] Huang L, Walter V, Hayes DN, et al.Hedgehog-GLI signaling inhibition suppresses tumor growth in squamous lung cancer[J]. Clin Cancer Res, 2014,20(6):1566-1575. DOI: 10.1158/1078-0432.CCR-13-2195. [13] Stecca B, Mas C, Clement V, et al.Melanomas require hedgehog-gli signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways[J]. Proc Natl Acad Sci USA, 2007,104(14):5895-5900. DOI: 10.1073/pnas. 0700776104. [14] Jalili A, Mertz KD, Romanov J, et al.NVP-LDE225, a potent and selective smoothened antagonist reduces melanoma growth in vitro and in vivo[J]. PLoS One, 2013,8(7):e69064. DOI: 10.1371/journal.pone.0069064. [15] Alexaki VI, Javelaud D, Van Kempen LC, et al.GLI2-mediated melanoma invasion and metastasis[J]. J Natl Cancer Inst, 2010,102(15):1148-1159. DOI: 10.1093/jnci/djq257. [16] Sato H, Murphy P, Giles S, et al.Visualizing expression patterns of Shh and Foxf1 genes in the foregut and lung buds by optical projection tomography[J]. Pediatr Surg Int, 2008,24(1):3-11. DOI: 10.1007/s00383-007-2036-1. [17] Pollom EL, Bui TT, Chang AL, et al.Concurrent vismodegib and radiotherapy for recurrent, advanced basal cell carcinoma[J]. JAMA Dermatol, 2015,151(9):998-1001. DOI: 10.1001/jamadermatol.2015.0326. [18] Wang K, Patel M, Prabhu AV, et al.First reported case of concurrent sonidegib and radiotherapy for recurrent, advanced basal cell carcinoma[J]. Rep Pract Oncol Radiother, 2021,26(1):149-152. DOI: 10.5603/RPOR.a2021.0010. [19] Jain S, Song R, Xie J.Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas[J]. Onco Targets Ther, 2017,10:1645-1653. DOI: 10.2147/OTT.S130910.
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