Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

Jain, Anisha; Prasad, Ashwini; Pradeep, Sushma; Dharmashekar, Chandan; Achar, Raghu Ram; Ekaterina, Silina; Victor, Stupin; Amachawadi, Raghavendra G.; Prasad, Shashanka K.; Pruthvish, R.; Syed, Asad; Shivamallu, Chandan; Kollur, Shiva Prasad

doi:10.3389/fonc.2021.741326

Cited by 22 publications

(18 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent evidences indicate that non-canonical signaling is important in oncogenesis via the interaction with PI3K, mTORC2, AKT, MAPK pathway, and HIF-1α in the cytoplasm and nuclear ( Ayaz and Osborne, 2014 ; Li et al, 2016 ; Zou et al, 2019 ; Qin et al, 2020 ). The MAPK pathway is activated in lung cancer and plays a critical role in the development and progression of cancer ( Fu et al, 2021 ; Hu et al, 2021 ; Jain et al, 2021 ; Shin et al, 2021 ). Our results showed that Notch4 silencing downregulated phosphorylation of ERK, JNK, and P38.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis

Li¹,

Cao²,

Zhao³

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Hypoxia contributes to the progression and metastasis of lung adenocarcinoma (LUAD). However, the specific underlying molecular mechanisms have not been fully elucidated. Here we report that Notch4 is upregulated in lung tissue from lung cancer patients. Functionally, Hypoxia activates the expressions of Delta-like 4 and Notch4, resulting in the excessive proliferation and migration of LUAD cells as well as apoptotic resistance. Notch4 silencing reduced ERK, JNK, and P38 activation. Meanwhile, Notch4 overexpression enhanced ERK, JNK, and P38 activation in LUAD cells. Furthermore, Notch4 exerted pro-proliferation, anti-apoptosis and pro-migration effects on LUAD cells that were partly reversed by the inhibitors of ERK, JNK, and p38. The binding interaction between Notch4 and ERK/JNK/P38 were confirmed by the co-immunoprecipitation assay. In vivo study revealed that Notch4 played a key role in the growth and metastasis of LUAD using two xenograft models. This study demonstrates that hypoxia activates Notch4-ERK/JNK/P38 MAPK signaling pathways to promote LUAD cell progression and metastasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis

Li¹,

Cao²,

Zhao³

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…The introduction of targeted medicines has revolutionized the treatment of patients with A-549 carcinoma. When combined with natural extracts with stratagems, repurposing non-cancer drugs into new therapeutic niches presents a cost-effective and efficient technique with enhanced outcomes for discovering novel pharmacological activity to potentially increase cure rates for lung and liver cancers [ 63 , 64 ].…”

Section: Resultsmentioning

confidence: 99%

Pomegranate Pomace Extract with Antioxidant, Anticancer, Antimicrobial, and Antiviral Activity Enhances the Quality of Strawberry-Yogurt Smoothie

et al. 2022

View full text Add to dashboard Cite

Valorizing the wastes of the food industry sector as additives in foods and beverages enhances human health and preserves the environment. In this study, pomegranate pomace (PP) was obtained from the company Schweppes and exposed to the production of polyphenols and fiber-enriched fractions, which were subsequently included in a strawberry-yogurt smoothie (SYS). The PP is rich in carbohydrates and fibers and has high water-absorption capacity (WAC) and oil-absorption capacity (OAC) values. The LC/MS phenolic profile of the PP extract indicated that punicalagin (199 g/L) was the main compound, followed by granatin B (60 g/L) and pedunculagin A (52 g/L). Because of the high phenolic content of PP extract, it (p ≤ 0.05) has high antioxidant activity with SC50 of 200 µg/mL, besides scavenging 95% of DPPH radicals compared to ascorbic acid (92%); consequently, it reduced lung cancer cell lines’ viability to 86%, and increased caspase-3 activity. Additionally, it inhibited the growth of pathogenic bacteria and fungi i.e., L. monocytogenes, P. aeruginosa, K. pneumonia, A. niger, and C. glabrata, in the 45–160 µg/mL concentration range while killing the tested isolates with 80–290 µg/mL concentrations. These isolates were selected based on the microbial count of spoiled smoothie samples and were identified at the gene level by 16S rRNA gene sequence analysis. The interaction between Spike and ACE2 was inhibited by 75.6%. The PP extract at four levels (0.4, 0.8, 1.2, and 1.4 mg/mL) was added to strawberry-yogurt smoothie formulations. During 2 months storage at 4 °C, the pH values, vitamin C, and total sugars of all SYS decreased. However, the decreases were gradually mitigated in PP-SYS because of the high phenolic content in the PP extract compared to the control. The PP-SYS3 and PP-SYS4 scored higher in flavor, color, and texture than in other samples. In contrast, acidity, fat, and total soluble solids (TSS) increased at the end of the storage period. High fat and TSS content are observed in PP-SYS because of the high fiber content in PP. The PP extract (1.2 and 1.6 mg/mL) decreases the color differences and reduces harmful microbes in PP-SYS compared to the control. Using pomegranate pomace as a source of polyphenols and fiber in functional foods enhances SYS’s physiochemical and sensory qualities.

show abstract

“…There was no evidence for in vitro or in vivo antitumoral effects of PHA-793887 in NSCLC. Although there is a line of evidence for drug repurposing for other antimalarial drugs such as hyroxychloroquine and artemisinin, 81 there was no indication of TGX-115 usage in NSCLC treatment. We could not find any cancer-associated literature for remaining small molecules Z-Leu3-VS, TGX-115, Ingenol 3,20-dibenzoate, Maprotiline hydrochloride, NTNCB hydrochloride, or Rottlerin.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis for Identification of Therapeutic Targets and Prognostic Signatures in Non-Small Cell Lung Cancer

Erkín

Comertpay

Göv

2022

Bioinform Biol Insights

View full text Add to dashboard Cite

Differential expressions of certain genes during tumorigenesis may serve to identify novel manageable targets in the clinic. In this work with an integrated bioinformatics approach, we analyzed public microarray datasets from Gene Expression Omnibus (GEO) to explore the key differentially expressed genes (DEGs) in non-small cell lung cancer (NSCLC). We identified a total of 984 common DEGs in 252 healthy and 254 NSCLC gene expression samples. The top 10 DEGs as a result of pathway enrichment and protein–protein interaction analysis were further investigated for their prognostic performances. Among these, we identified high expressions of CDC20, AURKA, CDK1, EZH2, and CDKN2A genes that were associated with significantly poorer overall survival in NSCLC patients. On the contrary, high mRNA expressions of CBL, FYN, LRKK2, and SOCS2 were associated with a significantly better prognosis. Furthermore, our drug target analysis for these hub genes suggests a potential use of Trichostatin A, Pracinostat, TGX-221, PHA-793887, AG-879, and IMD0354 antineoplastic agents to reverse the expression of these DEGs in NSCLC patients.

show abstract

Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

Cited by 22 publications

References 89 publications

Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis

Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis

Pomegranate Pomace Extract with Antioxidant, Anticancer, Antimicrobial, and Antiviral Activity Enhances the Quality of Strawberry-Yogurt Smoothie

Integrative Analysis for Identification of Therapeutic Targets and Prognostic Signatures in Non-Small Cell Lung Cancer

Contact Info

Product

Resources

About