期刊
LIFE SCIENCES
卷 230, 期 -, 页码 121-131出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2019.05.050
关键词
Theophylline; Melanoma; Cancer stem cells; Differentiation; Cytokines
资金
- ISS-Sapienza University PhD Fellowship
- European Molecular Biology Organization (EMBO)
- Fondazione Umberto Veronesi
- Ministry of Health, Italy [GR-2009-1570296]
- Ministry of Health, Italy (Oncotechnologic Program, Project Biobanca sieroproteomica)
- Ministry of Health, Italy (Italy-USA Oncoproteomic Program)
- Telethon Foundation [GTF08002]
- Region Occitanie [RCLE R14007BB, 12052802, RBIO R15070BB, 14054342]
- Laboratoire d'Excellence Toulouse Cancer (TOUCAN) [ANR11-LABX]
- Fondation Toulouse Cancer Sante [2014CS044]
Aims: Cutaneous melanoma is the most aggressive skin cancer, derived from neoplastic transformation of melanocytes. Since several evidences highlighted the importance of a hierarchical model of differentiation among cancer cells, closely related to resistance mechanisms and tumor relapse, we investigated the effects of theophylline (Theo), a methylxanthine commonly used in treatment of respiratory diseases, on melanoma cells with different degree of differentiation, including patient-derived melanoma-initiating cells. Materials and methods: The antiproliferative and antimetastatic effects of Theo was demonstrated by cell counting, adhesion and migration assays on A375 and SK-MEL-30 cells. Further, Theo ability to reduce cell growth was highly significant in A375-derived spheroids and in two patient-derived melanoma-initiating cells (MICs). In order to identify pathways potentially involved in the antineoplastic properties of Theo, a comparative mass spectrometry proteomic analysis was used. Then, melanin content, tyrosinase and tissue transglutaminase activities as differentiation markers and actin re-organization through confocal microscopy were evaluated. Furthermore, a secretome profile of MICs after Theo treatments was performed by multiplex immunoassay. Key findings: Obtained results demonstrate inhibitory effects of Theo on melanoma cell proliferation and migration, mainly in MICs, together with the induction of differentiation parameters. Moreover, our data indicate that the known anti-melanoma effect of Theo is due also to its ability to interfere with cytoskeleton dynamics and to induce the secretion of inflammatory molecules involved in recruitment of immunosuppressive cells in tumor microenvironment. Significance: Data strongly suggest that Theo supplement, either as drug or as dietary supply, may represent a potent additional weapon against melanoma.
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