Recent progress in TGF-β inhibitors for cancer therapy Huang, Cheng-Yi; Chung, Chih-Ling; Hu, Tsung-Hui ...
Biomedicine & pharmacotherapy,
February 2021, 2021-Feb, 2021-02-00, 20210201, 2021-02-01, Volume:
134
Journal Article
Peer reviewed
Open access
Display omitted
•Summary of the basic studies, patents, and clinical trials inhibiting TGF-β signalling, a critical pathway in tumorigenesis and fibrosis.•Small molecular inhibitors and neutralizing ...antibodies against TGF-β signaling are potential strategies for cancer therapy.•Natural products and repurposed drugs should continue to be major resources for screening TGF-β inhibitors.•The future prospect of new sources and mechanisms of TGF-β inhibitors are discussed in this review.
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is involved in proliferation, metastasis, and many other important processes in malignancy. Inhibitors targeting TGF-β have been considered by pharmaceutical companies for cancer therapy, and some of them are in clinical trial now. Unfortunately, several of these programs have recently been relinquished, and most companies that remain in the contest are progressing slowly and cautiously. This review summarizes the TGF-β signal transduction pathway, its roles in oncogenesis and fibrotic diseases, and advancements in antibodies and small-molecule inhibitors of TGF-β.
The mold
, also called red yeast rice, anka, or koji, has been used as the natural food coloring agent and food additives for more than 1000 years in Asian countries. It has also been used in Chinese ...herbology and traditional Chinese medicine due to its easing digestion and antiseptic effects. However, under different culture conditions, the ingredients in
-fermented products may be changed. Therefore, an in-depth understanding of the ingredients, as well as the bioactivities of
-derived natural products, is important. Here, through the thorough investigation into the chemical constituents of
wmd2424, five previously undescribed compounds, monascuspurins A-E (
-
), were isolated from the EtOAc extract of mangrove-derived fungus
wmd2424 cultured in RGY medium. All the constituents were confirmed via HRESIMS and 1D- and 2D-NMR spectroscopy. Their antifungal activity was also evaluated. Our results showed that four constituents (compounds
-
) possessed mild antifungal activity against
,
,
, and
. It is worth mentioning that the chemical composition of the type strain
wmd2424 has never been studied.
A series of flavanols were synthesized to assess their biological activity against human non-small cell lung cancer cells (A549). Among the sixteen synthesized compounds, it was observed that ...compounds
(3.14 ± 0.29 µM) and
(0.46 ± 0.02 µM) exhibited higher potency compared to 5-fluorouracil (5-Fu, 4.98 ± 0.41 µM), a clinical anticancer drug which was used as a positive control. Moreover, compound 6l (4'-bromoflavonol) markedly induced apoptosis of A549 cells through the mitochondrial- and caspase-3-dependent pathways. Consequently, compound
might be developed as a candidate for treating or preventing lung cancer.
Three new triterpenoids-spergulagenin B (
), spergulagenin C (
), and spergulagenin D (
)-were isolated from the aerial part of
, along with 17 known compounds (
-
). The structures of these new ...compounds were identified by spectroscopic and MS analyses. Compounds
,
,
, and
were evaluated for inhibition of nitric oxide production in LPS-stimulated RAW 264.7 cells with IC
values of 17.03, 18.21, 16.30, and 12.64 μM, respectively. Compounds
,
, and
exhibited inhibitory effects on LPS-induced nitric oxide production in RAW 264.7 cells with IC
values of 18.35 ± 1.34, 17.56 ± 1.41, and 14.27 ± 1.29 μM, respectively.
Three new compounds, 4-geranyloxy-2-hydroxy-6-isoprenyloxybenzophenone (
), hypericumone A (
) and hypericumone B (
), were obtained from the aerial parts of
, along with six known compounds (
-
). ...The structures of these compounds were determined through spectroscopic and MS analyses. Hypericumone A (
), sampsonione J (
) and otogirinin A (
) exhibited potent inhibition (IC
values ≤ 40.32 μM) against lipopolysaccharide (LPS)-induced nitric oxide (NO) generation. Otogirinin A (
) possessed the highest inhibitory effect on
production with IC
value of 32.87 ± 1.60 μM. The well-known proinflammatory cytokine
tumor necrosis factor-alpha (TNF-α) was also inhibited by otogirinin A (
). Western blot results demonstrated that otogirinin A (
) downregulated the high expression of inducible nitric oxide synthase (iNOS). Further investigations on the mechanism showed that otogirinin A (
) blocked the phosphorylation of MAPK/JNK and IκBα, whereas it showed no effect on the phosphorylation of MAPKs/ERK and p38. In addition, otogirinin A (
) stimulated anti-inflammatory M2 phenotype by elevating the expression of arginase 1 and Krüppel-like factor 4 (KLF4). The above results suggested that otogirinin A (
) could be considered as potential compound for further development of NO production-targeted anti-inflammatory agent.
is a well-known species for flavoring many food products and for formulation of perfume and medicated balm. It is also used to treat indigestion, stomach ulcers, liver disorders, and, as emmenagogue, ...diaphoretic, diuretic, nervine, and aphrodisiac. We examined antioxidant properties and bioactive compounds in various solvent extracts from the seeds of
. Methanol, ethanol, and acetone extracts exhibited relatively strong antioxidant activities by 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), superoxide radical, and hydroxyl radical scavenging tests. Furthermore, methanol extracts also displayed significant anti-α-glucosidase activity. Examined and compared to the various solvent extracts for their chemical compositions using HPLC analysis, we isolated the ten higher content compounds and analyzed antioxidant and anti-α-glucosidase activities. Among the isolates, dehydrodiisoeugenol, malabaricone B and malabaricone C were main antioxidant components in seeds of
. Malabaricone C exhibited stronger antioxidant capacities than others based on lower half inhibitory concentration (IC
) values in DPPH and ABTS radical scavenging assays, and it also showed significant inhibition of α-glucosidase. These results shown that methanol was found to be the most efficient solvent for extracting the active components from the seeds of
, and this material is a potential good source of natural antioxidant and α-glucosidase inhibitor.
Selenium is an essential micronutrient that is beneficial to human health. Selenium‐containing drugs have been developed as antioxidants, anti‐inflammatory, and anticancer agents. However, the ...synthesis of selenium‐containing chalcones has not been fully explored. Therefore, we report the synthesis of novel selenophene‐based chalcone analogs and reveal their biological activities as anticancer agents. Among the seven synthesized molecules, compounds 6, 8, and 10 exhibited anticancer activity with IC50 values of 19.98 ± 3.38, 38.23 ± 3.30, and 46.95 ± 5.68 μM, respectively, against human colorectal adenocarcinoma (HT‐29) cells. Clonogenic assays and Western blot analysis tests further confirmed that compound 6 effectively induced apoptosis in HT‐29 cells through mitochondrial‐ and caspase‐3‐dependent pathways.
Novel selenophene‐based chalcone analogs were synthesized and assessed for their biological activities as anticancer agents. Compound 6 showed more potent activity (IC50 = 19.98 ± 3.38 μM) against human colorectal adenocarcinoma cells (HT‐29) than 5‐fluorouracil (IC50 = 41.43 ± 7.90 μM) as a positive control.
Three new and uncommon chromone analogs, epiremisporine F (
), epiremisporine G (
), and epiremisporine H (
), were isolated from marine-origin
. Among the isolated compounds, compounds
-
remarkably ...suppressed fMLP-induced superoxide anion generation by human neutrophils, with IC
values of 31.68 ± 2.53, and 33.52 ± 0.42 μM, respectively. Compound
exhibited cytotoxic activities against human colon carcinoma (HT-29) and non-small lung cancer cell (A549) with IC
values of 21.17 ± 4.89 and 31.43 ± 3.01 μM, respectively, and Western blot assay confirmed that compound
obviously induced apoptosis of HT-29 cells, via Bcl-2, Bax, and caspase 3 signaling cascades.
The resinous wood of
, known as agarwood (
in Chinese), is traditionally used for the treatment of abdominal pain, vomiting, circulatory disorders, and dyspnea. Four new 2-(2-phenylethyl)-4
...-chromen-4-one derivatives, namely 7-methoxy-2-2-(4'-hydroxy-phenyl)ethylchromone (
), 7-hydroxy-2-2-(4'-methoxyphenyl)ethylchromone (
), 5,6-dihydroxy- 2-2-(3'-hydroxy-4'-methoxyphenyl)ethylchromone (
), and 6-hydroxy-5-methoxy-2-(2-phenyl-ethyl)chromone (
), have been isolated from the resinous wood of
, together with nine known compounds. The structures of these compounds were determined through spectroscopic and MS analyses. Among the isolated compounds, neopetasan, 7-methoxy-2-(2-phenylethyl)-chromone, 6,7-dimethoxy-2-(2-phenylethyl)chromone, and 6,7-dimethoxy-2-2-(4'-methoxy-phenyl)ethylchromone inhibited NF-κB activation in LPS-stimulated RAW 264.7 macrophages with relative luciferase activity values of 0.55 ± 0.09, 0.54 ± 0.03, 0.31 ± 0.05, and 0.38 ± 0.14, respectively, versus that of vehicle control (1.03 ± 0.02). In addition, 5,6-dihydroxy-2-2-(3'-hydroxy-4'-methoxyphenyl)ethylchromone, 7-methoxy-2-(2-phenylethyl)chromone, 7-dimethoxy-2-(2-phenylethyl)chromone, and 6,7-dimethoxy-2-2-(4'-methoxyphenyl)ethylchromone could suppress LPS-induced NO production in RAW 264.7 cells and did not induce cytotoxicity against RAW 264.7 cells after 24-h treatment.
Bioassay-guided fractionation of extracts derived from solid cultures of a Herbidospora daliensis originating from Taiwan led to the isolation of five new compounds, for which we propose the name ...herbidosporadalins A−E (1−5), one isolated for the first time, herbidosporadalin F (6), together with two known compounds (7 & 8). Their structures were elucidated by spectroscopic analyses, including 1D- and 2D-NMR experiments with those of known analogues, and on the basis of HR-EI-MS mass spectrometry, their anti-inflammatory activities were also evaluated. Of these isolates, herbidosporadalin A (1), B (2), F (6) and G (8) showed NO inhibitory activity, with IC50 values of 11.8 ± 0.9, 7.1 ± 2.9, 17.8 ± 1.7, and 13.3 ± 6.5 μM, stronger than the positive control quercetin (IC50 = 36.8 ± 1.3 μM). To the best of our knowledge, this is the first report on 3,4-seco-friedelane metabolites (5, 6 & 8) from the genus Herbidospora.
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