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

Argyris C Hadjimichael, Athanasios F Foukas, Olga D Savvidou, Andreas F Mavrogenis, Amanda K Psyrri, Panayiotis J Papagelopoulos, Argyris C Hadjimichael, Athanasios F Foukas, Olga D Savvidou, Andreas F Mavrogenis, Amanda K Psyrri, Panayiotis J Papagelopoulos

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.

Keywords: Doxycycline; Metalloproteinase; Metastasis; Osteosarcoma; VEGF.

Conflict of interest statement

Competing interestsNone of the authors have any competing interests.

© The Author(s) 2020.

Figures

Fig. 1
Fig. 1
The chemical structure of Doxycycline. The lower oxygen-rich part is able to form chelation bonds with MMPs [7]
Fig. 2
Fig. 2
The role of neo-angiogenesis for tumor metastasis from local to distant sites. (1) The local proliferation and expansion of primary osteosarcoma cells. (2) MMPs cause overexpression of VEGF leading to new blood vessels formation. (3) Degradation of extracellular matrix and basic membranes by MMPs help malignant cells to invade in blood vessels. (4) Osteosarcoma cells arrested from endothelial cells of blood vessels in distant organs. (5) Tumor cells migrate in distant sites following blood circulation where they adhere. (6) Secondary tumors secrete MMPs in order to form a sufficient neoplastic blood vessels network. (7) Osteosarcoma cells in distant tissues create mature metastatic tumors [4]
Fig. 3
Fig. 3
Mechanism of MMPs inactivation by Doxycycline. Osteosarcoma cells secrete MMPs which support survival and invasiveness of malignant cells. Doxycycline (DOX) inactivates MMPs by forming chelation bonds with their Zn2+ and Ca2+ ions [7]
Fig. 4
Fig. 4
The indirect anti-angiogenesis effect of Doxycycline via MMPs inhibition. MMPs increase the secretion of proangiogenic factors like VEGF, bFGF and TGF promoting the formation of new network of blood vessels. Adequate blood supply helps osteosarcoma cells to survive, proliferate and penetrate blood vessels to give metastases in distant organs, mainly in lungs. Doxycycline acts as a cytotoxic agent by inhibiting MMPs and depriving tumor cells from nutritional necessities [35]

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