Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer

Hashemzehi, Milad; Yavari, Negar; Rahmani, Farzad; Asgharzadeh, Fereshteh; Soleimani, Atena; Shakour, Neda; Avan, Amir; Hadizadeh, Farzin; Fakhraie, Maryam; Marjaneh, Reyhaneh Moradi; Ferns, Gordon A.; Reisi, Parham; Ryzhikov, Mikhail; Khazaei, Majid; Hassanian, Seyed Mahdi

doi:10.17179/excli2020-2932

Cited by 3 publications

(3 citation statements)

References 37 publications

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“…Several studies have indicated that TGF-β contributes to the promotion of fibrosis in cancers and other diseases, including a previous work by Hashemzehi et al 14 , 39 , 40 . Ballester et al and Li et al separately showed the anti-fibrotic effect of PFD acts through the inhibition of TGF-β1 and its downstream signaling mechanism 9 , 10 .…”

Section: Discussionmentioning

confidence: 94%

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Targeting transforming growth factor beta (TGF-β) using Pirfenidone, a potential repurposing therapeutic strategy in colorectal cancer

Jamialahmadi,

Nazari,

TanzadehPanah

et al. 2023

Sci Rep

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The modulating factors within the tumor microenvironment, for example, transforming growth factor beta (TGF-β), may limit the response to chemo and immunotherapy protocols in colorectal cancer (CRC). In the current study, the therapeutic potential of targeting the TGF-β pathway using Pirfenidone (PFD), a TGF-β inhibitor, either alone or in combination with five fluorouracil (5-FU) has been explored in preclinical models of CRC. The anti-proliferative and migratory effects of PFD were assessed by MTT and wound-healing assays respectively. Xenograft models were used to study the anti-tumor activity, histopathological, and side effects analysis. Targeting of TGF-β resulted in suppression of cell proliferation and migration, associated with modulation of survivin and MMP9/E-cadherin. Moreover, the PFD inhibited TGF-β induced tumor progression, fibrosis, and inflammatory response through perturbation of collagen and E-cadherin. Targeting the TGF-β pathway using PFD may increase the anti-tumor effects of 5-FU and reduce tumor development, providing a new therapeutic approach to CRC treatment.

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Section: Discussionmentioning

confidence: 94%

“…The multicellular spheroids were photographed after treatment with PFD, 5-FU, and their combination during the test (72 h). Spheroids parameters i.e., volume and diameter, were calculated with ImageJ software ( http://imagej.nih.gov/ij ) as previously described 14 , 15 .…”

Section: Methodsmentioning

confidence: 99%

Targeting transforming growth factor beta (TGF-β) using Pirfenidone, a potential repurposing therapeutic strategy in colorectal cancer

Jamialahmadi,

Nazari,

TanzadehPanah

et al. 2023

Sci Rep

Self Cite

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“…Further, Oridonin sensitizes HCC cells to the anticancer effects of Sorafenib administration by targeting the AKT pathway [ 165 ]. Neither clinical nor pre-clinical applications of OLT1177 compound have emerged in the GI cancer treatment at this time; instead, Tranilast inhibitor influences tumor growth and ameliorates fibrosis in CRC [ 166 ] and GC [ 167 ]; moreover, it suppresses esophageal cancer stem cells proliferation [ 168 ]. Although the above mentioned evidences, summarized in Fig.…”

Section: Nlrp3 Targeted Pharmacological Interventions In Gi Cancersmentioning

confidence: 99%

The ‘speck’-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis

Arrè,

Scialpi,

Centonze

et al. 2023

J Biomed Sci

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The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.

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Synthesis, Bioactivity Evaluation, and Molecular Docking Study of Tranilast Analogs as Anticancer Agents

Phan,

Pham,

Nguyen

et al. 2024

LOC

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Developing new agents with higher therapeutic potential and less toxicity to overcome the limitations of chemotherapy in cancer treatment has been identified as an urgent need and priority. Recent studies have shown promising anticancer activities of tranilast when used alone or in combination with other chemotherapeutic agents. This research aims to synthesize tranilast analogs, evaluate in vitro anticancer activity, and dock into the TGFβ1 target to find stronger anticancer agents. Tranilast (5a) and analogs (5b–f) were synthesized from anthranilic acid derivatives, Meldrum’s acid, and benzaldehydes based on the Knoevenagel-Doebner reaction. The compounds were evaluated for in vitro cytotoxicity activity by MTT assay and docked into the TGFβ1 target using AutoDockTools–1.5.6. Tranilast (5a) and seven analogs (5b–h) were successfully synthesized and analyzed for their structures. Four analogs (5b–d, 5f) possessed stronger effects on both HepG2 and MCF-7 cell lines with proliferation inhibitions at concentrations of 100 µg/mL in the range of 41 to 95% compared to tranilast (16.95% and 22.64%). Compound 5f exhibited the most potent analog with IC50 = 27.57 µg/mL (HepG2) and 16.67 µg/mL (MCF-7) compared to tranilast (IC50 > 100 µg/mL) and had good binding affinity on TGFβ1 target (docking score ˗7.35 Kcal/mol). Four of seven tranilast analogs possessed stronger cytotoxicity activity on both HepG2 and MCF-7 cell lines compared to that of the parent compound, tranilast. Notably, compound 5f displayed the most potent activity and good binding affinity on the TGFβ1 target, indicating the potential for further study as an anticancer agent.

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Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer

Cited by 3 publications

References 37 publications

Targeting transforming growth factor beta (TGF-β) using Pirfenidone, a potential repurposing therapeutic strategy in colorectal cancer

Targeting transforming growth factor beta (TGF-β) using Pirfenidone, a potential repurposing therapeutic strategy in colorectal cancer

The ‘speck’-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis

Synthesis, Bioactivity Evaluation, and Molecular Docking Study of Tranilast Analogs as Anticancer Agents

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