The potential role of nintedanib in treating colorectal cancer

Rossi, Antonio; Latiano, Tiziana Pia; Parente, Paola; Chiarazzo, Cinzia; Limosani, Filomena; Maggio, G. Di; Maiello, Evaristo

doi:10.1080/14656566.2017.1346086

Cited by 16 publications

(7 citation statements)

References 51 publications

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“…Figure 1 demonstrates some reported and FDA-approved VEGFR-2 inhibitors such as sorafenib I [34], sunitinib II [35], vorolanib III [36], nintedanib IV [37], and toceranib V [38]. These drugs have four key pharmacophoric features that must exist in any inhibitor to fit with the VEGFR-2 active site.…”

Section: Rationalementioning

confidence: 99%

The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

et al. 2022

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Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential of the designed compound was revealed via a molecular docking study that showed the appropriate binding. Then, MD simulation (six studies) over a period of 100 ns was performed to confirm the precise binding and optimum energy. Additionally, MM-GBSA reaffirmed the perfect binding, exhibiting a total precise energy of −40.38 Kcal/Mol. The MM-GBSA experiments named the essential amino acids in the protein–ligand interaction, employing the binding energy decomposition and revealing the diversity of interactions of compound 7 inside the VEGFR-2 enzyme. As compound 7 is new, DFT experiments were utilized for molecular structure optimization. Additionally, the DFT results validated the coherent interaction of compound 7 with the VEGFR-2 enzyme. A good value of drug-likeness of compound 7 was acknowledged via in silico ADMET studies. Interestingly, the experimental in vitro prohibitory potential of compound 7 was better than that of sorafenib, demonstrating an IC50 value of 25 nM. Notably, the strong inhibitory effects of compound 10 against two cancer cell lines (MCF-7 and HCT 116) were established with IC50 values of 12.93 and 11.52 μM, disclosing high selectivity indexes of 6.7 and 7.5, respectively.

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Section: Rationalementioning

confidence: 99%

The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

et al. 2022

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“…MMP-2 and MMP-9 are (gelatinase A, Type N collagenase) and (Gelatinase B, Type IV collagenase), respectively. MMP-2 and MMP-9 have ability to destroy the type IV of collagen, the MMP-2 and MMP-9 are the main compositions of membrane [95][96][97][98][99][100][101]. Studies showed that the activity of MMP-2 and MMP-9 is organized in pulmonary fibrosis [6].…”

Section: Firstly Injury Stagementioning

confidence: 99%

Corticosteroid Resistant Pulmonary Fibrosis: Pathophysiology and Management

Alghamdi¹,

Kawy²,

Damanhouri³

2021

JPRI

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Pulmonary fibrosis is a disease of the lower respiratory system. It might be as Idiopathic fibrosis which is obscure reason for disease or might be as an optional impact from different causes, for example, the environmental causes, for example, toxins and smoking, some connective tissue illnesses., infection diseases, for example, tuberculosis (TB) and corona virus, a few medications, for example, bleomycin, methotrexate, and radiation treatment. Glucocorticoid are used for treating inflammatory and immune diseases, like asthma, but interstitial lung disease, cystic fibrosis, and chronic obstructive pulmonary disease (COPD) at some stage, may become resistant to corticosteroid treatment. Glucocorticoids inhibit inflammation by many mechanisms. The oxidative stress leads to significantly decrease in activity and expression of Histone deacetylase 2 (HDAC-2) which causes resistant to the action of glucocorticoid. However, the dissociated glucocorticoids have been developed to decrease side effects, the dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of the desirable anti-inflammatory, immunosuppressive, or anticancer properties of classical glucocorticoid drugs with fewer side effects, but it is so difficult to dissociate anti-inflammatory effects from adverse effects. Patients with glucocorticoid resistance must use alternative anti-inflammatory treatments as well as drugs that may reverse the molecular mechanism of glucocorticoid resistant. Objective: This paper is to review the corticosteroid resistant pulmonary fibrosis and how overcome this resistance. The data was collected from December 2020 to September 2021.

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“…The multikinase inhibitor nintedanib, an anti-angiogenic inhibitor of VEGFR and PDGFR with anti-FGFR activity, in combination with chemotherapy has shown to be non inferior to bevacizumab-based regimen in metastatic colorectal cancer in a phase II clinical trial. Furthermore, even mCRC patients who were extensively pretreated benefited from nintedanib in terms of longer progression free survival and better quality of life [ 26 ]. Several additional multikinase inhibitors such as lucitanib (active against VEGFR1-3, PDGFRα/β and FGFR1-3), lenvatinib (E7080, Eisai; an inhibitor of FGFR, VEGFR, PDGFR, RET and KIT) or dovitinib (FGFR, VEGFR, PDGFR, CSF-1 and c-kit inhibitor) showed promising response rates in several phase I/II trials in breast cancer, solid tumors and renal carcinomas, respectively [ 27 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis

Fromme¹,

Schmitz²,

Wachter

et al. 2018

Oncotarget

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ObjectivesMetastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established.MethodsWe investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors (FGFR1-4) and their ligands (FGF3, 4 and 19) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ. Results were correlated with clinico-pathologic data and molecular subtypes.ResultsPrimary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111).ConclusionsWe provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.

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The potential role of nintedanib in treating colorectal cancer

Cited by 16 publications

References 51 publications

The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches

Corticosteroid Resistant Pulmonary Fibrosis: Pathophysiology and Management

FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis

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