Therapeutic effects of in vivo administration of an inhibitor of tryptophan 2,3-dioxygenase (680c91) for the treatment of fibroids: a preclinical study

Chuang, Tsai-Der; Ton, Nhu; Rysling, Shawn; Quintanilla, Derek; Boos, Drake; Khorram, Omid

doi:10.1016/j.fertnstert.2023.12.006

Fertility and Sterility

2024

DOI: 10.1016/j.fertnstert.2023.12.006

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Therapeutic effects of in vivo administration of an inhibitor of tryptophan 2,3-dioxygenase (680c91) for the treatment of fibroids: a preclinical study

Tsai-Der Chuang,

Nhu Ton,

Shawn Rysling

et al.

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2024

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Cited by 5 publications

References 38 publications

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The immune landscape of uterine fibroids as determined by mass cytometry

Boos,

Chuang,

Abbasi

et al. 2024

F&S Science

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The immune landscape of uterine fibroids as determined by mass cytometry

Boos,

Chuang,

Abbasi

et al. 2024

F&S Science

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Targeting the long non-coding RNA MIAT for the treatment of fibroids in an animal model

Chuang,

Ton,

Manrique

et al. 2024

Clinical Science

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Our previous studies indicated that there is overexpression of MIAT in fibroids and MIAT is a sponge for the miR-29 family in these tumors. The objective of this study was to determine if the knockdown of MIAT in fibroid xenografts will increase miR-29 levels and reduce the expression of genes targeted by this miRNA such as collagen and cell cycle regulatory proteins in a mouse model for fibroids. Ovariectomized CB-17 SCID/Beige mice bearing estrogen/progesterone pellets were implanted subcutaneously in the flank with equal weight of fibroid explants which had been transduced by lentivirus for either control (empty vector) or MIAT knockdown for four weeks (n=7). Knockdown of MIAT in fibroid xenografts resulted in a 30% reduction of tumor weight and a marked increase in miR-29a, -b, and -c levels in the xenografts. There was reduced cell proliferation and expression of cell cycle regulatory genes CCND1, CDK2, and E2F1 and no significant changes in apoptosis. The xenografts with MIAT knockdown expressed lower mRNA and protein levels of FN1, COL3A1, and TGF-β3, and total collagen protein. Targeting MIAT, which sponges the pro-fibrotic miR-29 family, is an effective therapy for fibroids by reducing cell proliferation and thereby, tumor growth and accumulation of ECM, which is a hallmark of these benign gynecologic tumors.

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The in vivo effects of knockdown of long non‐coding RNA XIST on fibroid growth and gene expression

Chuang,

Ton,

Rysling

et al. 2024

The FASEB Journal

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The role of long non‐coding RNAs in fibroid pathogenesis remains largely unexplored. In a previous study, we found elevated XIST (X‐inactive specific transcript) levels in fibroids, which sponged miR‐29c and miR‐200c, leading to the overexpression of their target genes. This study aimed to assess the therapeutic potential of XIST downregulation in fibroid treatment. Ovariectomized SCID (severe combined immunodeficiency) mice were implanted with fibroid tumors transduced with XIST siRNA or a control via lentivirus. After 1 month, animals were sacrificed and the xenografts were removed for further analysis. XIST knockdown reduced tumor weight by 15% and increased miR‐29c and miR‐200c expression by 3.9‐fold and 2.2‐fold, respectively. The mRNA expression of miR‐29c targets (COL3A1, TGF‐β3, CDK2, SPARC) and miR‐200c targets (CDK2, FN1, TDO2), as well as PRL, E2F1, and EZH2, was significantly decreased. Protein abundance of collagen, COL3A1, FN1, CDK2, SPARC, and EZH2 was also reduced. IHC analysis of xenograft sections using the markers of Ki67 for cell proliferation and cleaved caspase 3 for apoptosis showed decreased cell proliferation and no changes in apoptosis in the XIST knockdown xenografts. This analysis also revealed decreased collagen and E2F1 staining nuclei in the XIST knockdown xenografts. These results indicate that downregulation of XIST in fibroids has beneficial therapeutic effects, by reducing tumor growth and the expression of genes involved in cell proliferation, inflammation, and extracellular matrix regulation.

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Therapeutic effects of in vivo administration of an inhibitor of tryptophan 2,3-dioxygenase (680c91) for the treatment of fibroids: a preclinical study

Cited by 5 publications

References 38 publications

The immune landscape of uterine fibroids as determined by mass cytometry

The immune landscape of uterine fibroids as determined by mass cytometry

Targeting the long non-coding RNA MIAT for the treatment of fibroids in an animal model

The in vivo effects of knockdown of long non‐coding RNA XIST on fibroid growth and gene expression

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