| Reference | 1. J Leukoc Biol. 2017 Dec;102(6):1333-1345. doi: 10.1189/jlb.3RU0417-148RR. Epub
2017 Oct 6.
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The role of halofuginone in fibrosis: more to be explored?
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Luo Y(1), Xie X(1), Luo D(2), Wang Y(1), Gao Y(3).
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Author information: <br>
(1)Department of Stomatology, The Second Xiangya Hospital, Central South
University, Changsha, Hunan Province, China; and.
(2)Xiangya School of Stomatology, Central South University, Changsha, Hunan
Province, China.
(3)Department of Stomatology, The Second Xiangya Hospital, Central South
University, Changsha, Hunan Province, China; and [email protected].
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Fibrosis, which can be defined as an abnormal or excessive accumulation of
extracellular matrix (ECM), particularly fibrillar collagens, is a key driver of
progressive organ dysfunction in many inflammatory and metabolic diseases,
including idiopathic pulmonary fibrosis (IPF), cirrhosis, nephropathy, and oral
submucous fibrosis (OSF). It has been estimated to contribute to ～45% of deaths
in the developed world. Therefore, agents that target specific fibrotic pathways,
with the consequence of slowing, arresting, or even reversing the progression of
tissue fibrogenesis, are urgently needed.
7-Bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone
(halofuginone), an analog of febrifugine, which specifically targets the
pathogenesis of ECM proteins, inhibits tissue fibrosis and regeneration and even
affects the development of tumors in various tissues. Four modes of actions of
halofuginone against fibrosis have been presented: 1) Inhibition of mothers
against decapentaplegic homolog 3 (Smad3) phosphorylation downstream of the TGF-β
signaling pathway, 2) reduction of collagen amounts, 3) decreases in ECM protein,
and 4) selective prevention of Th17 cell differentiation. In this review, we will
mainly focus on the rationale for halofuginone against fibrosis.
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2. Histol Histopathol. 2011 Jan;26(1):135-46. doi: 10.14670/HH-26.135.
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Halofuginone and muscular dystrophy.
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Pines M(1), Halevy O.
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Author information: <br>
(1)Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
[email protected]
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Muscular dystrophies (MDs) include different inherited diseases that all result
in progressive muscle degeneration, impaired locomotion and often premature
death. The major focus of MD research has been on alleviating the primary genetic
deficit – using gene therapy and myoblast-transfer approaches to promote
expression of the deficient or mutated genes in the muscle fibers. Although
promising, these approaches have not yet entered into clinical practice and
unfortunately for MD patients, there is currently no cure. Thus, the development
of complementary and supportive therapies that slow disease progression and
improve patients/’ quality of life is critically important. The main features of
MDs are sarcolemmal instability and increased myofiber vulnerability to
mechanical stress, resulting in myofiber degeneration. Fibrosis, with progressive
replacement of muscle tissue, is a prominent feature in some MDs, preventing
complete regeneration and hampering muscle functions. TGFβ is the leading
candidate for activating fibroblasts and eliciting overproduction of
extracellular matrix (ECM) proteins. Halofuginone, an inhibitor of Smad3
phosphorylation downstream of TGFβ signaling, inhibits the activation of
fibroblasts and their ability to synthesize ECM, regardless of their origin or
location. In animal models of MDs with prominent muscle fibrosis, halofuginone
treatment has resulted in both prevention of collagen production in young animals
and resolution of established fibrosis in older ones: the reduction in muscle
collagen content was associated with improved muscle histopathology and major
improvements in muscle function. Recently, these halofuginone-dependent
improvements were also observed in MD with minor fibrosis involvement, probably
due to a direct effect of halofuginone on muscle cells, resulting in myotube
fusion that is dependent on Akt and MAPK pathway activation. In summary,
halofuginone improves muscle histopathology and muscle functions in various MDs,
via inhibition of muscle fibrosis on the one hand, and increased myotube fusion
on the other.
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3. Biol Blood Marrow Transplant. 2003 Jul;9(7):417-25.
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Halofuginone to treat fibrosis in chronic graft-versus-host disease and
scleroderma.
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Pines M(1), Snyder D, Yarkoni S, Nagler A.
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Author information: <br>
(1)Institute of Animal Science, ARO, the Volcani Center, Bet Dagan, 50250,
Israel. [email protected]
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Chronic graft-versus-host disease (cGvHD) and systemic sclerosis (scleroderma
[SSc]) share clinical characteristics, including skin and internal organ
fibrosis. Fibrosis, regardless of the cause, is characterized by extracellular
matrix deposition, of which collagen type I is the major constituent. The
progressive accumulation of connective tissue results in destruction of normal
tissue architecture and internal organ failure. In both SSc and cGvHD, the
severity of skin and internal organ fibrosis correlates with the clinical course
of the disease. Thus, there is an unmet need for well-tolerated antifibrotic
therapy. Halofuginone is an inhibitor of collagen type I synthesis in cells
derived from various tissues and species and in animal models of fibrosis in
which excess collagen is the hallmark of the disease. Halofuginone decreased
collagen synthesis in the tight skin mouse (Tsk) and murine cGvHD, the 2
experimental systems that show many features resembling those of human GvHD.
Inhibition of collagen synthesis by halofuginone is achieved by inhibiting
transforming growth factor beta-dependent Smad3 phosphorylation. Dermal
application of halofuginone caused a decrease in collagen content at the treated
site of a cGvHD patient, and reduction in skin scores was observed in a pilot
study with SSc patients. The results of the human studies provide basis for using
halofuginone treatment for dermal fibrosis. As a first step toward future
treatment of internal organ involvement, an oral administration study was
performed in which halofuginone was well tolerated and plasma levels surpassed
the predicted therapeutic exposure.
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