Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Combined cold atmospheric plasma and vemurafenib suppress MITF–P21 signaling and MMP‑driven metastasis in cutaneous melanoma

Articles in Press

Document Type : Original Article

Authors
Zahra Yazdani 1, 2
Mansooreh Mirzaei 3
Sadegh Fattahi 4
Farshad Sohbatzadeh 5
Saeid Abediankenari 6
Arefeh Moosavi 7
Fatemeh Mirbabae 7
Zeynab Rostami 1, 2
Monireh Golpour 8
Alireza Rafiei 1
1 Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
2 Students Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
3 Department of Anatomy, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
4 North Research Center, Pasteur Institute of Iran, Amol, Iran
5 Department of Atomic and Molecular Physics, Faculty of Science, University of Mazandaran, Babolsar, Iran
6 Immunogenetics Research Center, Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
7 Department of Basic Sciences, Sari Agricultural Sciences and Natural Resources University, Sari, Iran
8 Cancer Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
10.22038/ijbms.2026.95374.20566
Abstract
Objective(s): This study investigated the anti-tumor efficacy of combined cold atmospheric plasma (CAP) and Vemurafenib (VEM) treatment (CAP plus VEM) in cutaneous melanoma, focusing on the MITF–P21 axis and MMP‑driven metastasis.
Materials and Methods: The therapeutic effects of CAP and VEM were evaluated using in vitro and in vivo models. B16‑F10 melanoma and L929 fibroblast cell lines were used to assess long‑term cell proliferation and migration using clonogenic and wound‑healing assays. In vivo, melanoma tumors were induced in C57BL/6 mice, followed by treatment with CAP, VEM, or CAP plus VEM. Tumor tissues and major organs were collected for histopathological evaluation and molecular analysis. Gene expression levels of MITF, P21, MMP‑2, and MMP‑9 were quantified by qRT‑PCR in both experimental settings.
Results: CAP and VEM significantly inhibited melanoma cell proliferation and migration, with the CAP plus VEM showing the most pronounced effect. In vitro, all treatments markedly down-regulated MITF, P21, and MMP-2 gene expression (P<0.0001). Histopathological analysis revealed extensive tumor necrosis, reduced cellularity, and improved tissue architecture in the CAP plus VEM group, accompanied by fewer metastatic alterations in major organs. qRT‑PCR of tumor tissues confirmed significant down-regulation of MMP‑2 and MMP‑9 after CAP, VEM, and especially the CAP plus VEM group (P<0.0001). The modest in vivo changes in MITF and P21 may reflect microenvironmental influences.
Conclusion: The CAP plus VEM enhances anti-tumor efficacy and suppresses metastasis‑related pathways in melanoma, both in vitro and in vivo. This suggests a promising complementary therapeutic strategy.
Keywords
Animal
In vitro
In vivo
Melanoma
Matrix metalloproteinases Models
Plasma gases
Vemurafenib
Subjects
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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 19 August 2026