The anti-neoplastic effect of doxycycline in osteosarcoma as a metalloproteinase (MMP) inhibitor: a systematic review

Abstract

Background: Osteosarcoma is a very aggressive primary bone tumour, affecting mainly young populations. Most cases diagnosed have distant macro-and micro-metastases at the time of diagnosis. Surgical resection with neoadjuvant and adjuvant therapies improves the overall and disease-free survival of patients. Doxycycline, a synthetic tetracycline, has been found to act either as an antibiotic drug or as a chemotherapeutic agent. Its anti-neoplastic role has been found to be significant, in vitro and in vivo laboratory trials, in various types of cancer, such as prostate, intestinal, central neural system cancers and osteosarcoma. Inhibition of metalloproteinases (MMPs) in different stages of tumour expansion is the most well-understood mechanism. MMPs are secreted molecules from various normal cells, such as fibroblasts, leucocytes and vascular smooth muscles, as well as from cells with high proliferative potential, such as tumour cells. In osteosarcoma, MMPs have been found to be overexpressed. MMPs help osteosarcoma cells survive, grow and produce metastases in distant sites, mainly in the lungs. Doxycycline blocks extracellular matrix and basic membrane degradation by suppressing MMP function. As a consequence, osteosarcoma cells lose their ability to invade and metastasize. Additionally, doxycycline eliminates the secretion of vascular endothelial growth factor (VEGF) and deprives the supply of circulating nutrients by its anti-angiogenesis action. The aim of this review is to evaluate doxycycline's action against osteosarcoma cells as an MMP-inhibitor and interpret its usage as a chemotherapeutic agent. Methods: We checked PubMed and Google Scholar for recently published data, on the tumour-supportive role of MMPs and VEGF in osteosarcoma cells. We further studied published experimental trials on the role of doxycycline as a tumour-suppressive agent via MMPs and VEGF inhibition. Results: MMPs and VEGF have been found to play a fundamental role in osteosarcoma cells survival and high aggressiveness by in vitro, in vivo and clinical trials. Nevertheless, doxycycline has proved its tumour-suppressive effect by in vivo experimental trials in various cancers but not yet in osteosarcoma. Conclusion: Doxycycline remains a promising chemotherapeutic agent against osteosarcoma via MMP inhibition, showing the need for further in vivo and clinical trials to be carried out in the future.

Role of Integrin αvβ3 in Doxycycline-Induced Anti-Proliferation in Breast Cancer Cells

“…Those observations suggested that autophagy inhibited by doxycycline may be in part due to the effects on expression of stem cell markers, EMT, and proliferation (Zhang et al, 2017). Doxycycline is verified to block cancer cell progression by different mechanisms (Sagar et al, 2010;Hadjimichael et al, 2020;Yi et al, 2021). The previous studies have shown that doxycycline suppresses MMP expression and FAK phosphorylation to inhibit leukemic cell migration (Wang et al, 2015).…”

Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations

“…In GBM, overexpressed MMP helps tumor cells to survive, grow, and metastasize in distant sites [101], participating in the disruption and tumor neovascularization. Thus, the angiogenic response can be directly or indirectly mediated by MMPs through modulating the balance between pro-and anti-angiogenic factors [102].…”

Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

“…The anticancer effects of doxycycline and COL-3, semisynthetic and chemically modified tetracycline, respectively, were mainly related to their inhibitory effects on the expression and activation of matrix metalloproteases (166,167). In fact, doxycycline and COL-3 exert antiangiogenic and antimetastatic activity in different cancer cell lines including leukemias, osteosarcoma, breast, colorectal and prostate cancer (166,(168)(169)(170)(171)(172).…”