Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Dev, Sareshma Sudhesh; Abidin, Syafiq Asnawi Zainal; Farghadani, Reyhaneh; Othman, Iekhsan; Naidu, Rakesh

doi:10.3389/fphar.2021.772510

Cited by 73 publications

(55 citation statements)

References 352 publications

(428 reference statements)

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“…There are three major oncogenic signaling pathways that drive cell growth, proliferation and metabolism of cells: the PI3K/AKT/mTOR (PI3K pathway), RAS/RAF/ERK (MAPK pathway), and STAT/JAK pathways [ 7 ] ( Fig. 2 ).…”

Section: Drug Resistancementioning

confidence: 99%

“…Drugs have been developed with a wide range of mechanisms of action. One of the most common drug mechanisms is the inhibition of tyrosine phosphorylation of target proteins by small molecule TKIs that compete with ATP-binding to the tyrosine kinase domain of proteins and thereby block protein phosphorylation and inhibit the proliferation and oncogenic signals through a number of signaling pathways such as the RAS-MAPK (mitogen-activated protein kinase), PI3K (phosphoinositide 3-kinase)-AKT-mTOR (mammalian target of rapamycin), and JAK/STAT pathways [ 7 ]. Drugs like osimertinib, alectinib, larotrectinib, crizotinib, among others are in this class.…”

Section: Introductionmentioning

confidence: 99%

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Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer

2022

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Precision oncology has fundamentally changed how we diagnose and treat cancer. In recent years, there has been a significant change in the management of patients with oncogeneaddicted advanced-stage NSCLC. Increasing amounts of identifiable oncogene drivers have led to the development of molecularly targeted drugs. Undoubtedly, the future of thoracic oncology is shifting toward increased molecular testing and the use of targeted therapies. For the most part, these novel drugs have proven to be safe and effective. As with all great innovations, targeted therapies pose unique challenges. Drug toxicities, resistance, access, and costs are some of the expected obstacles that will need to be addressed. This review highlights some of the major challenges in the use of targeted therapies in NSCLC and provides guidance for the future strategies.

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Section: Drug Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer

2022

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“…TKIs are inhibitors that bind to receptor tyrosine kinases and inhibit their function, and examples of these receptors include EGFR, AKT, c-MET, VEGFR and MEK1/2 [ 68 ]. It is only in recent few years that the exosome-mediated acquired resistance against several TKIs has been characterized in sufficient detail [ 69 , 70 ].…”

Section: Mechanisms Of Exosome-mediated Cancer Drug Resistancementioning

confidence: 99%

Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

Khan

Alsayed

Choudhry

et al. 2022

IJMS

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Exosomes, the extracellular vesicles produced in the endosomal compartments, facilitate the transportation of proteins as well as nucleic acids. Epigenetic modifications are now considered important for fine-tuning the response of cancer cells to various therapies, and the acquired resistance against targeted therapies often involves dysregulated epigenetic modifications. Depending on the constitution of their cargo, exosomes can affect several epigenetic events, thus impacting post-transcriptional regulations. Thus, a role of exosomes as facilitators of epigenetic modifications has come under increased scrutiny in recent years. Exosomes can deliver methyltransferases to recipient cells and, more importantly, non-coding RNAs, particularly microRNAs (miRNAs), represent an important exosome cargo that can affect the expression of several oncogenes and tumor suppressors, with a resulting impact on cancer therapy resistance. Exosomes often harbor other non-coding RNAs, such as long non-coding RNAs and circular RNAs that support resistance. The exosome-mediated transfer of all this cargo between cancer cells and their surrounding cells, especially tumor-associated macrophages and cancer-associated fibroblasts, has a profound effect on the sensitivity of cancer cells to several chemotherapeutics. This review focuses on the exosome-induced modulation of epigenetic events with resulting impact on sensitivity of cancer cells to various therapies, such as, tamoxifen, cisplatin, gemcitabine and tyrosine kinase inhibitors. A better understanding of the mechanisms by which exosomes can modulate response to therapy in cancer cells is critical for the development of novel therapeutic strategies to target cancer drug resistance.

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“…Receptor tyrosine kinases (RTKs) are involved in various processes, including cell proliferation, survival, migration, invasion, and other cancer-related processes. Abnormalities in RTK activation have been linked to disease progression in various human cancers, making them promising drug targets for cancer treatment [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling

et al. 2022

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Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the downregulation of c-Met by artonin F, a flavonoid isolated from Artocarpus gomezianus. Artonin F was found to be dominantly toxic to lung cancer cells by mediating apoptosis. With regard to its mechanism of action, artonin F downregulated c-Met expression, consequently suppressed the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling, increased Bax expression, decreased Bcl-2 expression, and activated caspase-3. The depletion of c-Met was mediated by ubiquitin-proteasomal degradation following co-treatment with artonin F, with the proteasome inhibitor MG132 reversing its c-Met-targeting effect. The immunoprecipitation analysis revealed that artonin F significantly promoted the formation of the c-Met–ubiquitin complex. Given that ubiquitin-specific protease 8 (USP8) prevents c-Met degradation by deubiquitination, we performed a preliminary in silico molecular docking and observed that artonin F blocked the catalytic site of USP8. In addition, artonin F interacted with the catalytic residues of palmitoylating enzymes. By acting as a competitive inhibitor, artonin F could reduce the degree of palmitoylation of c-Met, which affected its stability and activity. In conclusion, c-Met is critical for cancer cell survival and the failure of chemotherapeutic regimens. This novel information on the c-Met downregulating effect of artonin F will be beneficial for the development of efficient anticancer strategies or targeted therapies.

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Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

Cited by 73 publications

References 352 publications

Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer

Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer

Exosome-Mediated Response to Cancer Therapy: Modulation of Epigenetic Machinery

Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling

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