The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis
Open accessAbstract
with ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases.
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“This increased stiffness is an important survival signal for myofibroblasts; via mechanosensing such stiffness results in intracellular activation of Rho and Rho-associated kinase (ROCK) whose activity increases BCL2-XL expression (36).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [36]
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“Recently, it has been shown that pharmacological inhibition of BCL2-XL can mimic this process and induce targeted BIM-mediated apoptosis in myofibroblasts and even revert established (murine) fibrosis (36).”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [36]
In the citing paper
“Importantly, this increased, stiffness-induced, BCL2-XL expression is needed to counteract the function of the pro-apoptotic protein BIM (36). BIM is an activator of BAX and accumulates in myofibroblasts exposed to a stiff matrix. This accumulation primes the cells to undergo apoptosis (36), and only the continued presence of BCL2-XL prevents this.”
From Unraveling SSc Pathophysiology; The Myofibroblast (2018) · cites this paper as [36]
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Cites
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An inhibitor of Bcl-2 family proteins induces regression of solid tumours
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Self-citationControl of apoptosis by the BCL-2 protein family: implications for physiology and therapy
Czabotar, P. E., Lessene, G., Strasser, A., & Adams, J. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3722 · Cited by 3,219
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
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ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
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Mitochondria as multifaceted regulators of cell death
Bock, F. J., & Tait, S. W. G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0173-8 · Cited by 2,531
Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine
Dey, A., Varelas, X., & Guan, K.-L. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0070-z · Cited by 860
Self-citationEvasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases
Hinz, B., & Lagares, D. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0324-5 · Cited by 642
Self-citationCancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment
Liu, T., Zhou, L., Li, D., Andl, T., & Zhang, Y. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00060 · Cited by 446
“Navitoclax (ABT-263) is a small molecule that was shown to have the ability to induce apoptosis in myofibroblasts (Lagares et al., 2017).”
BackgroundGibb, A., Lazaropoulos, M. P., & Elrod, J. W. (2020) · Circulation Research · doi:10.1161/circresaha.120.316958 · Cited by 467
Metadata
- Authors
- Lagares, D., Santos, A., Grasberger, P. E., Liu, F., Probst, C. K., Rahimi, R. A., Sakai, N., Kuehl, T., Ryan, J., Bhola, P., Montero, J., Kapoor, M., Baron, M., Varelas, X., Tschumperlin, D. J., Letai, A., & Tager, A. M.
- Affiliations
- Harvard University (US)
- Fibrosis Research Center and Center for Immunology and Inflammatory Diseases, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
- University Health Network (CA)
- Jewish General Hospital (CA)
- Boston University (US)
- Mayo Clinic (US)
- Corresponding author
- Lagares, David
- Santos, Alba
- Grasberger, Paula E.
- Tager, Andrew M.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2017-12-13
- Volume
- 9
- Issue
- 420
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC8520471
- OpenAlex
- W2774171294
- Cited by
- 246
- References
- 63
- Citations by year
- 2026: 31 · 2025: 25 · 2024: 30 · 2023: 36 · 2022: 21 · 2021: 34 · 2020: 28 · 2019: 23 · 2018: 17 · 2017: 1
- FWCI
- 14.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (2r01hl092961-13)
- National Heart, Lung, and Blood Institute (R01-HL-092961, R01HL108975, K08HL140173)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Sclerosis and Related Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- navitoclax, BH3 mimetics, myofibroblast apoptosis, systemic sclerosis, skin fibrosis, fibrosis reversal, mitochondrial priming, BH3 profiling, anti-apoptotic proteins, drug response prediction
- MeSH terms
- Aniline Compounds, Animals, Biomechanical Phenomena, Cell Survival, Disease Models, Animal, Extracellular Matrix, Fibrosis, Humans, Male, Mice, Inbred C57BL, Mitochondria, Scleroderma, Systemic, Sulfonamides, Signal Transduction, Apoptosis, Dermis, Mechanotransduction, Cellular, bcl-X Protein, Mitochondrial Membranes, Myofibroblasts
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