Co-encapsulated nanoparticles of Erlotinib and Quercetin for targeting lung cancer through nuclear EGFR and PI3K/AKT inhibition

Ganthala, Parimala Devi; Alavala, Sateesh; Chella, Naveen; Andugulapati, Sai Balaji; Babu, Bathini Nagendra; Sistla, Ramakrishna

doi:10.1016/j.colsurfb.2021.112305

Cited by 35 publications

(17 citation statements)

References 24 publications

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“…Quercetin displays a synergistic efficacy when used in combination with several anti-cancer drugs. The combined use of erlotinib and quercetin was shown to be more effective against A549 and NCI H460 cells than combinations of erlotinib with fisetin, carnosic acid, or luteolin [34]. In addition, erlotinib-quercetin nanoparticles significantly inhibited the expression of p-EGFR/PI3K/p-AKT protein in erlotinib-resistant A549/ER lung cancer cells in vitro and in vivo [34].…”

Section: Discussionmentioning

confidence: 97%

Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2)

Chan

Hong

Chang

et al. 2023

Cells

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Oral squamous cell carcinoma (OSCC) frequently carries high epidermal growth factor receptor (EGFR) expression. Erlotinib, a small molecule tyrosine kinase inhibitor (TKI), is an effective inhibitor of EGFR activity; however, resistance to this drug can occur, limiting therapeutic outcomes. Therefore, in the current study, we aimed to unveil key intracellular molecules and adjuvant reagents to overcome erlotinib resistance. First, two HSC-3-derived erlotinib-resistant cell lines, ERL-R5 and ERL-R10, were established; both exhibited relatively higher growth rates, glucose utilization, epithelial-mesenchymal transition (EMT), and invasiveness compared with parental cells. Cancer aggressiveness-related proteins, such as N-cadherin, Vimentin, Twist, MMP-2, MMP-9, and MMP-13, and the glycolytic enzymes PKM2 and GLUT1 were upregulated in ERL-R cells. Notably, ERL-R cells were sensitive to quercetin, a naturally-existing flavonol phytochemical with anti-cancer properties against various cancer cells. At a concentration of 5 μM, quercetin effectively arrested cell growth, reduced glucose utilization, and inhibited cellular invasiveness. An ERL-R5-derived xenograft mouse model confirmed the growth-inhibitory efficacy of quercetin. Additionally, knock-down of PKM2 by siRNA mimicked the effect of quercetin and re-sensitized ERL-R cells to erlotinib. Furthermore, adding quercetin blocked the development of erlotinib-mediated resistance by enhancing apoptosis. In conclusion, our data support the application of quercetin in anti-erlotinib-resistant OSCC and indicate that PKM2 is a determinant factor in erlotinib resistance and quercetin sensitivity.

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Section: Discussionmentioning

confidence: 97%

Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2)

Chan

Hong

Chang

et al. 2023

Cells

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“…In EGFR mutant NSCLC, activated EGFR induced PD-L1 expression through PI3K/AKT1 and MAPK signaling pathways ( Luo et al, 2021 ), which is in accord with KEGG pathway analysis ( Figure 5 ). In recent years, the inhibitory effects of quercetin, luteolin, kaempferol, wogonin, baicalein and acacetin on EGFR have been reported in literature ( Wenzel et al, 2001 ; Hong et al, 2014 ; Liu et al, 2016b ; Yao et al, 2016 ; Tian et al, 2021 ; Ganthala et al, 2022 ). Furthermore, JUN (jun proto-oncogene, c-Jun) is the key component of dimeric transcription factor AP-1 involved in regulation of PD-L1 expression and activation of CD8 + T cells ( Atsaves et al, 2019 ; Papavassiliou and Musti, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Qingfei Jiedu decoction inhibits PD-L1 expression in lung adenocarcinoma based on network pharmacology analysis, molecular docking and experimental verification

et al. 2022

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Objective: We aim at investigating the molecular mechanisms through which the Qingfei Jiedu decoction (QFJDD) regulates PD-L1 expression in lung adenocarcinoma (LUAD).Methods: Bioactive compounds and targets of QFJDD were screened from TCMSP, BATMAN-TCM, and literature. Then, GeneCard, OMIM, PharmGKB, Therapeutic Target, and DrugBank databases were used to identify LUAD-related genes. The protein-protein interaction (PPI) network was constructed using overlapping targets of bioactive compounds in LUAD with the Cytoscape software and STRING database. The potential functions and pathways in which the hub genes were enriched by GO, KEGG, and DAVID pathway analyses. Molecular docking of bioactive compounds and key genes was executed via AutoDock Vina. Qualitative and quantitative analyses of QFJDD were performed using UPLC-Q-TOF-MS and UPLC. Expressions of key genes were determined by qRT-PCR, immunoreactivity score (IRS) of PD-L1 was assessed by immunohistochemistry (IHC), while the CD8+PD-1+T% derived from spleen tissues of Lewis lung cancer (LLC) bearing-mice was calculated using flow cytometry (FCM).Results: A total of 53 bioactive compounds and 288 targets of QFJDD as well as 8151 LUAD associated genes were obtained. Further, six bioactive compounds, including quercetin, luteolin, kaempferol, wogonin, baicalein, and acacetin, and 22 hub genes were identified. The GO analysis showed that the hub genes were mainly enriched in DNA or RNA transcription. KEGG and DAVID pathway analyses revealed that 20 hub genes were primarily enriched in virus, cancer, immune, endocrine, and cardiovascular pathways. The EGFR, JUN, RELA, HIF1A, NFKBIA, AKT1, MAPK1, and MAPK14 hub genes were identified as key genes in PD-L1 expression and PD-1 checkpoint pathway. Moreover, ideal affinity and regions were identified between core compounds and key genes. Notably, QFJDD downregulated EGFR, JUN, RELA, HIF1A, NFKBIA, and CD274 expressions (p < 0.05), while it upregulated AKT1 and MAPK1 (p < 0.05) levels in A549 cells. The PD-L1 IRS of LLC tissue in the QFJDD high dose (Hd) group was lower than model group (p < 0.01). CD8+PD-1+T% was higher in the QFJDD Hd group than in normal and model groups (p < 0.05).Conclusion: QFJDD downregulates PD-L1 expression and increases CD8+PD-1+T% via regulating HIF-1, EGFR, JUN and NFκB signaling pathways. Therefore, QFJDD is a potential treatment option for LUAD.

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“…Supported by the rapid advancement of nanomedicine, these inhibitor-loaded nanoparticles are showing improved bioavailability, prolonged blood circulation, enhanced tumor accumulation and reduced off-target side effects, leading to significant augmentation of therapeutic efficacy [ 41 , 42 ] supporting their continued development.…”

Section: Receptor-mediated Active Targeting Strategymentioning

confidence: 99%

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

et al. 2022

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Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice.

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Co-encapsulated nanoparticles of Erlotinib and Quercetin for targeting lung cancer through nuclear EGFR and PI3K/AKT inhibition

Cited by 35 publications

References 24 publications

Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2)

Oral Squamous Cell Carcinoma Cells with Acquired Resistance to Erlotinib Are Sensitive to Anti-Cancer Effect of Quercetin via Pyruvate Kinase M2 (PKM2)

Qingfei Jiedu decoction inhibits PD-L1 expression in lung adenocarcinoma based on network pharmacology analysis, molecular docking and experimental verification

Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies

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