Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Shay, Gemma; Tauro, Marilena; Loiodice, Fulvio; Tortorella, Paolo; Sullivan, Daniel M.; Hazlehurst, Lori A.; Lynch, Conor C.

doi:10.18632/oncotarget.18103

Cited by 16 publications

(13 citation statements)

References 51 publications

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“…New approaches such as targeting enzyme exosites or sub site pockets show promise for the continued development of next generation, “ultraselective” MMP inhibitors [69] , [70] , [71] . More recently, work combining a bisphosphonate backbone with an MMP inhibitor has produced bone seeking MMP inhibitors for selective delivery of MMP-2 inhibitor to the tumor-bone microenvironment, thereby circumventing off-target effects [72] , [73] .…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis

Frieling

Tauro

et al. 2020

Neoplasia

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Bone metastatic prostate cancer significantly impacts patient quality of life and overall survival, and despite available therapies, it is presently incurable with an unmet need for improved treatment options. As mediators of tumor progression, matrix metalloproteinases (MMPs) can degrade extracellular matrix components and regulate growth factor and cytokine bioactivity. Depending on tissue context, MMPs can either promote or inhibit tumorigenesis. Therefore, it is essential to study individual MMPs in specific cancer contexts and microenvironments to support the design and application of selective MMP inhibitors. Here we report that tumor-derived MMP-3 contributes to bone metastatic prostate cancer progression via intrinsic and extrinsic routes. MMP-3 ablation in prostate cancer cell lines significantly reduced in vitro growth combined with lowered AKT and ERK phosphorylation and total VEGFR1 and FGFR3 protein levels. In vivo , MMP-3 ablated tumors grew at a slower rate and were significantly less vascularized. Quantitative PCR analyses of wild type and MMP-3 silenced prostate cancer cells also demonstrate downregulation of a wide array of angiogenic factors. The extrinsic role for MMP-3 in angiogenesis was supported by in vitro endothelial tube formation assays where the lack of MMP-3 in prostate cancer conditioned media resulted in slower rates of tube formation. Taken together, our results suggest that tumor-derived MMP-3 contributes to prostate cancer growth in bone. These data indicate that selective inhibition of MMP-3 and/or targeting MMP generated products could be efficacious for the treatment of prostate to bone metastases.

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Section: Discussionmentioning

confidence: 99%

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis

Frieling

Tauro

et al. 2020

Neoplasia

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“…All animal experiments were performed in accordance with the guidelines of the Florida Atlantic University Institutional Animal Care and Use Committee (IACUC), protocol number A18‐04. Osteoclastogenesis was performed as previously described [32] . Briefly, whole bone marrow was flushed from both tibia and femur in hind limbs of either male or female mice.…”

Section: Methodsmentioning

confidence: 99%

Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability

et al. 2021

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Matrix metalloproteinase 13 (MMP‐13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP‐13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP‐13 action, we previously described a highly efficacious and selective MMP‐13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP‐13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP‐13‐mediated osteoclastogenesis but spared collagenolysis, and thus represents a next‐generation MMP‐13 probe applicable for in vivo studies of breast cancer metastasis.

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“…Regarding the mechanistic action of miR-29b-3p, it exerts its function by directly targeting the transcription factor FOS and MMP2 metalloproteinase. MMP2 metalloproteinase is overexpressed in the bone marrow of MM patients and is associated with MM progression [ 49 ]. FOS represents a vital transcription factor in osteoclastic differentiation and forms a regulatory positive feedback loop with RANK and NFKB1 [ 50 ].…”

Section: Mirnas As Signaling Pathway Regulators In Mmbdmentioning

confidence: 99%

Multiple Myeloma Bone Disease: Implication of MicroRNAs in Its Molecular Background

Παπανώτα

Karousi

Kontos

et al. 2021

IJMS

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Multiple myeloma (MM) is a common hematological malignancy arising from terminally differentiated plasma cells. In the majority of cases, symptomatic disease is characterized by the presence of bone disease. Multiple myeloma bone disease (MMBD) is a result of an imbalance in the bone-remodeling process that leads to increased osteoclast activity and decreased osteoblast activity. The molecular background of MMBD appears intriguingly complex, as several signaling pathways and cell-to-cell interactions are implicated in the pathophysiology of MMBD. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate the expression of their target mRNAs. Numerous miRNAs have been witnessed to be involved in cancer and hematological malignancies and their role has been characterized either as oncogenic or oncosuppressive. Recently, scientific research turned towards miRNAs as regulators of MMBD. Scientific data support that miRNAs finely regulate the majority of the signaling pathways implicated in MMBD. In this review, we provide concise information regarding the molecular pathways with a significant role in MMBD and the miRNAs implicated in their regulation. Moreover, we discuss their utility as molecular biomarkers and highlight the putative usage of miRNAs as novel molecular targets for targeted therapy in MMBD.

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Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Cited by 16 publications

References 51 publications

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis

Prostate cancer-derived MMP-3 controls intrinsic cell growth and extrinsic angiogenesis

Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability

Multiple Myeloma Bone Disease: Implication of MicroRNAs in Its Molecular Background

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