Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice

Merentie, Mari; Rissanen, Riina; Lottonen-Raikaslehto, Line; Huusko, Jenni; Gurzeler, Erika; Turunen, Mikko P.; Holappa, Lari; Mäkinen, Petri; Ylä‐Herttuala, Seppo

doi:10.1371/journal.pone.0190981

Cited by 15 publications

(16 citation statements)

References 40 publications

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“…According to Merentie et al doxycycline reduced the expression of VEGF in endothelial cells in vitro in a dose-dependent manner, but failed to downregulate its expression in transgenic mice in vivo [38]. In contrast, doxycycline has been found to eliminate angiogenesis indirectly as an MMP-9 inhibitor via suppression of VEGF expression in cerebral matrix of a mouse model [39].…”

Section: Anti-angiogenetic Effect Of Doxycycline Via Mmp-inhibitionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Anti-angiogenetic Effect Of Doxycycline Via Mmp-inhibitionmentioning

confidence: 99%

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

et al. 2020

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“…This dose of doxycycline was sufficient to induce cre in mice as per previous reports. 28 Wild-type (WT) mice were doxycycline treated GSK3β f/f mice. Male WT and GSK3β-KO mouse littermates were subjected to sham or I/R and sacrificed on Day 3, 6, and 9 after I/R.…”

Section: Study 4: I/r-induced Aki In Renal Tubule-specific Gsk3β Gementioning

confidence: 99%

Glycogen synthase kinase‐3β inhibits tubular regeneration in acute kidney injury by a FoxM1‐dependent mechanism

et al. 2020

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Acute kidney injury (AKI) is characterized by injury to the tubular epithelium that leads to the sudden loss of renal function. Proper tubular regeneration is essential to prevent progression to chronic kidney disease. In this study, we examined the role of FoxM1, a forkhead box family member transcription factor in tubular repair after AKI. Renal FoxM1 expression increased after renal ischemia/reperfusion (I/R)‐induced AKI in mouse kidneys. Treatment with thiostrepton, a FoxM1 inhibitor, reduced FoxM1 regulated pro‐proliferative factors and cell proliferation in vitro, and tubular regeneration in mouse kidneys after AKI. Glycogen synthase kinase‐3 (GSK3) was found to be an upstream regulator of FoxM1 because GSK3 inhibition or renal tubular GSK3β gene deletion significantly increased FoxM1 expression, and improved tubular repair and renal function. GSK3 inactivation increased β‐catenin, Cyclin D1, and c‐Myc, and reduced cell cycle inhibitors p21 and p27. Importantly, thiostrepton treatment abolished the improved tubular repair in GSK3β knockout mice following AKI. These results demonstrate that FoxM1 is important for renal tubular regeneration following AKI and that GSK3β suppresses tubular repair by inhibiting FoxM1.

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“…According to Merentie M. et al, doxycycline reduced the expression of VEGF in endothelial cells in vitro with a dose dependent manner, but failed to downregulate its expression in transgenic mice in vivo 37 . In contrast, doxycycline has been found to eliminate angiogenesis indirectly as an MMP-9 inhibitor, via suppression of VEGF expression in cerebral matrix of a mouse model 38 .…”

Section: Anti-angiogenetic Effect Of Doxycycline Via Mmp-inhibitionmentioning

confidence: 99%

The anti-neoplastic effect of Doxycycline in Osteosarcoma as a Metalloproteinase (MMP)-inhibitor. A systematic review

Hadjimichael

Foukas

Savvidou

et al. 2019

Preprint

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Background Osteosarcoma is as a very aggressive primary bone tumor, 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 improve overall and disease-free survival of patients. Doxycycline, a synthetic tetracycline has been found to act either as an antibiotic drug as well as a chemotherapeutic agent. Its anti-neoplastic role has been proven to be extremely significant in various types of cancer like prostate, intestinal, central neural system cancers and osteosarcoma. Inhibition of metalloproteinases (MMPs) in different stages of tumor expansion is the most well understood mechanism. MMPs are secreted molecules from various normal cells like fibroblasts, leucocytes and vascular smooth muscles but also from cells with high proliferative potential like tumor cells. In osteosarcoma, MMPs have been found to be overexpressed. MMPs help osteosarcoma cells to survive, grow and give metastases in distant sites, mainly in lungs. Doxycycline, blocks extracellular matrix and basic membranes degradation by suppressing MMPs function. As a consequence, osteosarcoma cells lose their ability to invade and give metastases. Additionally, doxycycline eliminates the secretion of vascular endothelial growth factor (VEGF) and deprives the supply of circulating nutritious components, 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 recent published data, on the tumor-supportive role of MMPs and VEGF in osteosarcoma cells. We further studied published experimental trials, on the role of doxycycline as a tumor-suppressive agent via MMPs and VEGF inhibition. Results MMPs and VEGF have been found to play a fundamental role in osteosarcoma cells survival and its high aggressiveness by in vitro, in vivo and clinical trials. Nevertheless, Doxycycline proved its tumor-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 MMPs inhibition, showing of the need, for further in vivo and clinical trials to carried out in the future. Key Words: Osteosarcoma, Metalloproteinase, VEGF, Doxycycline, Metastasis

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Doxycycline modulates VEGF-A expression: Failure of doxycycline-inducible lentivirus shRNA vector to knockdown VEGF-A expression in transgenic mice

Cited by 15 publications

References 40 publications

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

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

Glycogen synthase kinase‐3β inhibits tubular regeneration in acute kidney injury by a FoxM1‐dependent mechanism

The anti-neoplastic effect of Doxycycline in Osteosarcoma as a Metalloproteinase (MMP)-inhibitor. A systematic review

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