The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb

Autor: Eszter Molnár, Luca Hegedűs, József Tímár, Balázs Hegedűs, Imre Varga, Tamás Garay, Dominika Rittler, Marcell Baranyi, József Tóvári, István Jalsovszky, Clemens Aigner
Rok vydání: 2019
Předmět:
MAPK/ERK pathway
Medizin
Apoptosis
urologic and male genital diseases
lcsh:Chemistry
Phosphatidylinositol 3-Kinases
chemistry.chemical_compound
lcsh:QH301-705.5
Spectroscopy
Bone Density Conservation Agents
Diphosphonates
lipophilic bisphosphonate
biology
Melanoma
Cell Cycle
General Medicine
Computer Science Applications
Growth inhibition
Signal Transduction
RHEB
Cell Survival
Rheb
Antineoplastic Agents
Article
Catalysis
Inorganic Chemistry
In vivo
Cell Line
Tumor
melanoma
medicine
Animals
Humans
Physical and Theoretical Chemistry
Clonogenic assay
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Monomeric GTP-Binding Proteins
Organic Chemistry
medicine.disease
Xenograft Model Antitumor Assays
Disease Models
Animal
lcsh:Biology (General)
lcsh:QD1-999
chemistry
Cancer research
biology.protein
Proto-Oncogene Proteins c-akt
prenylation inhibition
Biomarkers
Zdroj: International Journal of Molecular Sciences
Volume 20
Issue 19
International Journal of Molecular Sciences, Vol 20, Iss 19, p 4917 (2019)
ISSN: 1422-0067
DOI: 10.3390/ijms20194917
Popis: Malignant melanoma is one of the most metastatic cancer types, and despite recent success with novel treatment strategies, there is still a group of patients who do not respond to any therapies. Earlier, the prenylation inhibitor hydrophilic bisphosphonate zoledronic acid (ZA) was found to inhibit melanoma growth in vitro, but only a weaker effect was observed in vivo due to its hydrophilic properties. Recently, lipophilic bisphosphonates (such as BPH1222) were developed. Accordingly, for the first time, we compared the effect of BPH1222 to ZA in eight melanoma lines using viability, cell-cycle, clonogenic and spheroid assays, videomicroscopy, immunoblot, and xenograft experiments. Based on 2D and spheroid assays, the majority of cell lines were more sensitive to BPH. The activation of Akt and S6 proteins, but not Erk, was inhibited by BPH. Additionally, BPH had a stronger apoptotic effect than ZA, and the changes of Rheb showed a correlation with apoptosis. In vitro, only M24met cells were more sensitive to ZA than to BPH
however, in vivo growth of M24met was inhibited more strongly by BPH. Here, we present that lipophilic BPH is more effective on melanoma cells than ZA and identify the PI3K pathway, particularly Rheb as an important mediator of growth inhibition.
Databáze: OpenAIRE
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