Sirajudheen Anwar
Nafees Ahmed
Letizia Giampietro- 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail, Saudi Arabia
- 2School of Pharmacy, Monash University Malaysia, Bandar Sunway, Selangor, Malaysia
- 3Department of Pharmacy, University G. d’Annunzio, Chieti, Italy
Editorial on the Research Topic
Targeting tumor EMT-related signaling by natural products
Natural products represent a good resource for antitumor agents and an excellent starting point for the synthesis of natural compound derivatives, useful for the treatment of various types of cancer (Giampietro et al., 2021; Naeem et al., 2022). These include natural products from plant, marine, animal etc. (Anwar et al., 2022).
In the last few years, many natural products and their derivatives have been explored as cytotoxic, antiproliferative or antioxidant agents and have also shown antitumor effects in preclinical and clinical research (Boretti, 2022). In comparison to synthetic medications, natural compounds have a higher amount of stiffness, which enhances protein cross-talk. This leads to better fitting into the protein receptor, which helps in easy protein activation for efficient signalling. They are the ideal candidates against cancer due to their diversity and adaptable structure complexity, a special natural property for biological activities such as that of artemisinin and vincristine. (Atanasov et al., 2021). This unique property of natural compounds had led the researchers to improve the knowledge to explore how they affect the tumour microenvironment and tumour signalling pathways.
In particular, epithelial-mesenchymal transition (EMT) represents an actual goal for the study of the tumor progression. EMT is a biological process during which epithelial cells are converted in mesenchymal cells. In physiological conditions, EMT regulates different biological activity such as wound repair, embryogenesis and organ development (Huang et al., 2022). In atypical circumstances, EMT occurs during the normal physiological tissue repair process, leading to angiogenesis, fibrosis, loss of function, and carcinoma. EMT has been associated with the development of invasive and cancer stem cells in carcinomas. EMT is triggered by transcription factors, which comprise the core helix-loop-helix factors TWIST1 and TWIST2, as well as SNAIL (SNAI1) and SLUG (SNAI2). Natural products could provide unprecedented hope in the fight against EMT and expand therapeutic alternatives. E-cadherin and other epithelial-related proteins and genes might be upregulated as part of a natural compound’s EMT targeting strategy, whereas mesenchymal phenotypes like vimentin, fibronectin 1, and N-Cadherin could be downregulated (Anwar et al., 2022).
With this in mind, Liang et al. studied in vivo and in vitro effect of natural compound, methyl gallate (MG) in hepatocellular carcinoma (HCC). In this research, for the first time, it was demonstrated that MG inhibits the proliferation, migration, invasion, and the EMT of HCC cells by regulating matrix metalloproteinases (MMPs) and adenosine monophosphate-activated protein kinase AMPK/NF-κB pathway, particularly upregulated epithelial E-cadherin protein and downregulated mesenchymal vimentin protein. This study revealed that the natural compound MG may have potential to affect EMT and treat cancer.
An important study by Cao et al. demonstrates that total flavonoid aglycones extract (TFAE) isolated from Scutellaria baicalensis inhibits tumor growth and induces apoptosis. In particular, the researchers showed that baicalein, wogonin, and oroxylin-A were the active compounds of TFAE and obtained the reconstructed TFAE (reTFAE) that was able to inhibit the EMT process in A549 cells. In this study, the relationship between reTFAE and PI3K/Akt signaling pathways, with TWIST1 as the key protein, was elucidated by using bioinformatic technology. Moreover, stable isotope dimethyl-labelled proteomics technology was conducted to complement the follow-up mechanism that EMT-inhibition process may be realized through the glycolysis pathway demonstrating that TWIST1-targeted flavonoids could provide a new strategy to inhibit EMT progress for the treatment of non-small cell lung cancer (NSCLC).
Another use of natural compounds in anticancer therapy was studied by Kang et al. In this study, Coptidis Rhizoma 30% ethanol extract (CRE) was evaluated as antimetastatic agent showing a significant inhibition of HCT116/R cells migration and invasion. CRE showed a potential ability to inhibit cancer metastasis via the suppression of EMT in drug-resistant cells especially in Colorectal cancer (CRC). The mechanism of action consists of upregulation of the expression of an epithelial marker (E-cadherin) and downregulation of the expression of mesenchymal markers (vimentin, Snail, and ZEB2) at both the protein and gene levels. Moreover, anti-EMT activity of CRE and its related effects were associated with the CRE-mediated suppression of the TGF-β pathway, as shown by changes in the levels of downstream molecules (phosphorylated Akt and p38), and inhibition of migration, invasion, and protein expression of TGF-β after treatment/cotreatment with a TGF-β inhibitor (SB431542). In this research, berberine was found as a main component of CRE, and it was supposed that it might be a prime contributor to stop the EMT process. This study lays the foundations to consider Coptidis Rhizoma or berberine as therapeutic candidates for the treatment of metastasis and drug resistance in CRC.
Among different natural compounds studied for the prevention of various cancer, Gossypol showed antitumor effects against different carcinoma from 1984 (Tuszynski and Cossu, 1984) along with few adverse reactions such as hypokalemia, loss of appetite, nausea and other gastrointestinal effects. For these reasons, recently a gossypol derivative, apogossypolone (ApoG2), lacking two aldehyde groups, was studied as antitumor compound. In this context, Li et al. demonstrated that ApoG2 suppress significantly the cervical cancer (CC) cell proliferation, invasion and EMT process in vitro and in vivo.
Another natural compound possessing antioxidant activity and used in therapy and prevention of inflammatory diseases and cancer is caffeic acid (CA); it is present in many herbs, vegetables, and fruits. Alam et al. published an important review where the therapeutic potential of CA in cancer is reported. The authors reported that the anticancer activity of CA is mainly due to its prooxidant, and antioxidant properties connected with the prevention of reactive oxygen species formation, the decrease of the angiogenesis of cancer cells, the enhance of the tumor cells’ DNA oxidation, and the repression of MMP-2 and MMP-9. These effects were referred to many cancer types demonstrated by in vivo and in vitro tests. It was concluded that CA alone or in combination with other chemotherapeutic agents might be used to treat cancer.
In conclusion, this Research Topic highlights some of the more important and key aspects of the use of natural compounds and their derivatives in the treatment of cancer. In particular, in this Research Topic, targeting tumor EMT-related signalling pathway by natural products was reported pointing out the importance of this aspect by in vivo and in vivo studies. Original research and the review in this Research Topic help to understand the molecular mechanisms behind the antitumor effects of natural products useful to promote the development of promising therapeutic strategies. In the future, researchers will be able to identify natural compounds that act as EMT inhibitors, enhancing the chemosensitivity of cancer cells resistant to chemotherapy while preventing metastasis.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Acknowledgments
We are grateful to all authors for their valuable contributions to this Research Topic. We are also thankful to the reviewers for their valuable suggestions and constructive comments to improve the quality of published manuscripts. We are also grateful to Frontiers in Pharmacology for inviting to edit this Research Topic.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
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Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., and Supuran, C. T. (2021). Natural products in drug discovery: Advances and opportunities. Nat. Rev. Drug Discov. 20, 200–216. doi:10.1038/s41573-020-00114-z
Boretti, A. (2022). Natural products as cancer chemo preventive agents: Where we stand. Nat. Product. Commun. 17 (12), 1934578X2211445–8. doi:10.1177/1934578x221144579
Giampietro, L., Gallorini, M., Gambacorta, N., Ammazzalorso, A., De Filippis, B., Della Valle, A., et al. (2021). Synthesis, structure-activity relationships and molecular docking studies of phenyldiazenyl sulfonamides as aromatase inhibitors. Eur. J. Med. Chem. 224, 113737. doi:10.1016/j.ejmech.2021.113737
Huang, Y., Hong, W., and Wei, X. (2022). The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J. Hematol. Oncol. 15, 129. doi:10.1186/s13045-022-01347-8
Naeem, A., Hu, P., Yang, M., Zhang, J., Liu, Y., Zhu, W., et al. (2022). Natural products as anticancer agents: Current status and future perspectives. Molecules 27, 8367. doi:10.3390/molecules27238367
Keywords: natural products, epithelial-mesenchymal transition (EMT), targeting tumor, treatment of cancer, EMT inhibitors
Citation: Anwar S, Ahmed N and Giampietro L (2023) Editorial: Targeting tumor EMT-related signaling by natural products. Front. Pharmacol. 14:1152328. doi: 10.3389/fphar.2023.1152328
Received: 27 January 2023; Accepted: 13 February 2023;
Published: 20 February 2023.
Edited and reviewed by:
Olivier Feron, Université catholique de Louvain, BelgiumCopyright © 2023 Anwar, Ahmed and Giampietro. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Letizia Giampietro, letizia.giampietro@unich.it