Doxycycline inhibits the progression of metastases in early-stage osteosarcoma by downregulating the expression of MMPs, VEGF and ezrin at primary sites

Hadjimichael, Argyris C.; Foukas, Athanasios F.; Papadimitriou, Εvangelia; Kaspiris, Angelos; Peristiani, Chrysostomi; Chaniotakis, Ioannis E.; Kotsari, Maria; Pergaris, Alexandros; Theocharis, Stamatios; Sarantis, Panagiotis; Christopoulou, Magdalini; Psyrri, Amanda; Mavrogenis, Andreas F.; Savvidou, Olga D.; Papagelopoulos, Panayiotis J.; Armakolas, Athanasios

doi:10.1016/j.ctarc.2022.100617

Cited by 4 publications

(3 citation statements)

References 70 publications

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“…In pulmonary metastases of osteosarcoma, doxycycline affects macrophage polarization by skewing the tumor induced M2-like TAMs to anti-tumor M1-like subsets, through this mechanism it prevents the progress of pulmonary micro-metastases to macro-metastases at early-stage disease. ( Hadjimichael et al, 2022 ). Table 5 illustrates studies investigating the effects of OXPHOS-targeted drugs on TAMs.…”

Section: Introductionmentioning

confidence: 99%

Metabolic vulnerability of cancer stem cells and their niche

Marrone,

Romano,

Malasomma

et al. 2024

Front. Pharmacol.

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Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.

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Section: Introductionmentioning

confidence: 99%

Metabolic vulnerability of cancer stem cells and their niche

Marrone,

Romano,

Malasomma

et al. 2024

Front. Pharmacol.

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“…It interrupts bacterial protein synthesis via inhibiting the binding of aminoacyl-tRNA to the ribosome in bacterial cell. In addition, recent studies reveal its anti-cancer property through inhibiting the activity and production of matrix metalloproteinases (MMPs), 10,11 or disturbing mitochondrial function in some types of cancer cells. 12,13 Osteosarcoma is the most common bone cancer and mainly occurs in children and adolescents.…”

Section: Introductionmentioning

confidence: 99%

Acute generation of reactive oxygen species that induced by doxycycline pretreatment results in rapid cell death in polyphyllin G‐treated osteosarcoma cell lines

Chen

Hsieh

et al. 2023

Environmental Toxicology

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Polyphyllin G, a pennogenyl saponin extracted from Paris polyphylla, has been shown to possess antitumor effects. In this study, we demonstrated that doxycycline, an antibiotic medicine, could significantly enhance the sensitivities of osteosarcoma cell lines to polyphyllin G. As the cells were pretreated with doxycycline at non-toxic concentrations and then co-exposed to polyphyllin G, this combination could induce a rapid cell death distinct from apoptosis. The non-apoptotic cell death was characterized by a loss of integrity of plasma membrane without externalization of phosphatidyl serine. Furthermore, this combined treatment resulted in suppression of cell viability and colony-forming ability, and increased the level of γ-H2A.X, a critical marker for DNA damage, in osteosarcoma cell lines. When examining the underlying mechanism, it was revealed combination of polyphyllin G and doxycycline triggered an enhanced generation of reactive oxygen species (ROS), and up-regulated mitochondrial oxidative stress within 0.5 h. Co-administration of the ROS inhibitor NAC reversed the suppressed cell viability and colony-forming ability, and abolished the increased level of γ-H2A.X in the cells with the combined treatment, indicating that the enhanced ROS was involved in the anti-proliferative effect of the combined treatment. Overall, the results demonstrated that doxycycline may function as chemosensitizers by inducing an acute and lethal ROS production to enhance cytotoxic of Shih-Chieh Hung and Yi-Fu Huang contributed equally to this study.

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“…Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents [ 1 , 2 ]. At the initial diagnosis, about 10–15% of OS patients were found to have lung metastasis, and up to 80% of patients were found to have lung micro-metastasis [ 3 , 4 ]. Currently, surgical removal and neoadjuvant chemotherapy are the mainstays of OS treatment.…”

Section: Introductionmentioning

confidence: 99%

CD248 promotes migration and metastasis of osteosarcoma through ITGB1-mediated FAK-paxillin pathway activation

Lü

Zhang

et al. 2023

BMC Cancer

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Background Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. Methods We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. Results CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. Conclusion Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS.

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Doxycycline inhibits the progression of metastases in early-stage osteosarcoma by downregulating the expression of MMPs, VEGF and ezrin at primary sites

Cited by 4 publications

References 70 publications

Metabolic vulnerability of cancer stem cells and their niche

Metabolic vulnerability of cancer stem cells and their niche

Acute generation of reactive oxygen species that induced by doxycycline pretreatment results in rapid cell death in polyphyllin G‐treated osteosarcoma cell lines

CD248 promotes migration and metastasis of osteosarcoma through ITGB1-mediated FAK-paxillin pathway activation

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