Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-β signaling

Kano, Mitsunobu R.; Bae, Younsoo; Iwata, Caname; Morishita, Yasuyuki; Yashiro, Masakazu; Oka, Masako; Fujii, Tomoaki; Komuro, Akiyoshi; Kiyono, Kunihiko; Kaminishi, Michio; Hirakawa, Kosei; Ouchi, Yasuyoshi; Nishiyama, Nobuhiro; Kataoka, Kazunori; Miyazono, Kohei

doi:10.1073/pnas.0611660104

Cited by 391 publications

(301 citation statements)

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“…5,6,11 Ki26894 was mixed with normal powdered food (CE-2; CLEA, Hamamatsu, Shizuoka, Japan) to a final concentration of 0.08%, and was orally administered to caveolin 3-deficient transgenic mice (CAV3 P104L ) or control wild-type mice aged between 6 and 16 weeks, as described. 18 All animal experiments were performed at the Laboratory Animal Center and were approved by the Animal Research Committee of Kawasaki Medical School.…”

Section: Animals and Administration Of Ki26894mentioning

confidence: 99%

“…Ki26894 was orally administered in the food to 10-week-old wild-type mice as previously described. 18 Sera from 12-week-old wild-type mice fed with or without Ki26894 for 2 weeks were added to the culture media of HEK293 cells transfected with a luciferase reporter gene (n ¼ 10; Supplementary Figure 1). Recombinant myostatin-induced luciferase activity was decreased to 19% by adding sera from Ki26894-fed mice to the culture media to a final concentration of 25%.…”

Section: Administration Of An Oral Tbri Kinase Inhibitor Enhances Myomentioning

confidence: 99%

“…[17][18][19][20] A204 human rhabdomyosarcoma cells or HEK293 human embryonic kidney cells were transfected with pGL3-(CAGA) 12 luciferase, a TGF-b-sensitive Smad-responsive luciferase reporter gene. 21 Stimulation of these cells with recombinant myostatin, activin A, or TGF-b1 caused a significant increase in luciferase activity above the basal level (A204: Figure 1a-c; HEK293: Figure 1d-f).…”

Section: Tbri Kinase Inhibitors Broadly Suppress the In-vitro Transcrmentioning

confidence: 99%

“…The NcoI-SalI fragment of green fluorescent protein (GFP) cDNA in the original pMXs-IRES-GFP retroviral vector 22 was substituted with the Cherry cDNA fragment derived from the pmCherry-N1 plasmid vector (Clontech, Mountain View, CA, USA). One microgram of total RNA from mouse skeletal muscle was reverse transcribed with an oligo(dT) [12][13][14][15][16][17][18] primer and subjected to PCR using the following primers: myostatin, 5 0 -CGGGATC-CATGATGCAAAAACTG-3 0 and 5 0 -CGGAATTCTCATGAG-CACCCAC-3 0 ; activin A, 5 0 -CGGAATTCATGCCCTTGCTT TGG-3 0 and 5 0 -CGCTCGAGCTAGGAGCAGCCAC-3 0 ; TGF-b1, 5 0 -CGGAATTCATGCCGCCCTCGGGG-3 0 and 5 0 -CGCTCGAGTCAGCTGCACTTGC-3 0 . The resulting PCR products were then cloned into the pMXs-IRES-Cherry vector using the appropriate restriction sites.…”

Section: Construction Of Retroviral Vectorsmentioning

confidence: 99%

“…12 TbRI kinase inhibitors have been found to suppress tumor enlargement and metastasis in the advanced stages of cancer in animals. [15][16][17][18] Notably, these inhibitors also suppress a similar kinase domain of ALK4, the type I receptor for activin, and potentially block ALK4/5, the type I receptor for myostatin. 1,12,19,20 However, the impact and clinical significance of TbRI kinase inhibitors on the skeletal muscle signaling of activin, myostatin, and TGF-b1-3 is unknown.…”

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confidence: 99%

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An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

Ohsawa

Okada

Nishimatsu

et al. 2012

Laboratory Investigation

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Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3 P104L ) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-b) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-b type I receptor (TbRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-b1, -b2, and -b3 signaling. Here, we show that a TbRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-b1, as well as CAV3 P104L . Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3 P104L mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-b family members in muscle. These data indicate that both TGF-b-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TbRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-b signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.

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Section: Animals and Administration Of Ki26894mentioning

confidence: 99%

Section: Administration Of An Oral Tbri Kinase Inhibitor Enhances Myomentioning

confidence: 99%