Natural Secondary Metabolites for Cancer Therapeutics: Discovery of New, Selective and Safe Drug Leads

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: closed (10 January 2024) | Viewed by 8365

Special Issue Editors


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Guest Editor
Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia
Interests: phytochemotaxonomy; natural products; genetic diversity; metabolic disorders; carcinoma
Department of Biology, College of Science, University of Hail, Hail P.O. Box 2440, Saudi Arabia
Interests: natural products; phytomedicine; bioactive metabolites; plant-based therapies; cancer genomics
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Guest Editor
Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara 391760, India
Interests: natural products; bioactive metabolites; phytotherapies; anticancer agents; phytochemistry

Special Issue Information

Dear Colleagues,

Despite decades of research and extensive efforts, cancer remains one of the top causes of death in the world, accounting for approximately 10 million deaths worldwide or one of every six deaths in 2020 according to the World Health Organization. Men are more likely to be affected by lung, prostate, colorectal, stomach, and liver cancers, whereas women are more prone to breast, colorectal, lung, cervical, and thyroid cancers. Globally, the cancer burden continues to grow, exerting enormous pressure on individuals, families, communities, and healthcare systems on a physical, emotional, and financial level. Many cancer patients around the world do not have access to timely diagnosis and quality treatment because the health systems of low- and middle-income countries are ill-prepared to handle this burden. Accordingly, there is still an urgent need to develop and discover novel anticancer drugs and treatment options to combat this disease.

Secondary metabolites produced by plants, animals, fungi, and microorganisms have been used for centuries as potent therapeutic agents for their interesting properties as poisons, dyes, antimicrobials, insecticides, and flavoring agents, and they may also be useful in preventing the onset of cancer. Therefore, this Special Issue aims to publish original articles as well as interesting review articles on the isolation or the investigation of mechanisms of action of secondary metabolites with potential anticancer activity. Manuscripts must provide insights, strategies, and advancements in the development of secondary-metabolite-based cancer therapeutics targeting various types of human cancers with minimal or no side effects. In vitro, in vivo, and in silico studies involved in the development of novel natural secondary metabolites that are effective as cancer therapeutics are welcome. For pharmacological studies, appropriate positive controls should be included, as well as, if possible, nontumorigenic cells, for comparison purposes. For in silico studies, at least one bench experimental datum (wet studies) is required to support and validate the conclusions. In studies conducted on natural extracts, secondary metabolites must be characterized in the extracts before the results are presented. This Special Issue will cover topics including, but not limited to, the following:

  • Bioactive secondary metabolites for targeted cancer therapy.
  • Detailed mechanistic studies on the anticancer activity of secondary metabolites as a new lead in cancer therapy. 
  • Identification of potent and selective bioactive secondary metabolites through in silico, in vitro, and in vivo approaches for the discovery and development of inhibitors as emerging cancer therapeutics targeting various signaling pathways, transcription factors, and cellular activities associated with cancer development.

Prof. Dr. Fevzi Bardakci
Dr. Mohd Adnan
Dr. Mitesh Patel
Guest Editors

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Keywords

  • bioactive secondary metabolites
  • cancer therapeutics
  • drug discovery
  • natural products
  • marine secondary metabolites
  • plant secondary metabolites
  • microbial secondary metabolites

Published Papers (4 papers)

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Research

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19 pages, 3232 KiB  
Article
Ethanolic Extract of Artemisia vulgaris Leaf Promotes Apoptotic Cell Death in Non-Small-Cell Lung Carcinoma A549 Cells through Inhibition of the Wnt Signaling Pathway
by Rohit Kumar Tiwari, Afza Ahmad, Ahamad Faiz Khan, Lamya Ahmed Al-Keridis, Mohd Saeed, Nawaf Alshammari, Nadiyah M. Alabdallah, Irfan Ahmad Ansari and Farina Mujeeb
Metabolites 2023, 13(4), 480; https://doi.org/10.3390/metabo13040480 - 27 Mar 2023
Cited by 4 | Viewed by 1771
Abstract
The Wnt signaling pathway is reported to be associated with lung cancer progression, metastasis and drug resistance, and thus it is an important therapeutic target for lung cancer. Plants have been shown as reservoirs of multiple potential anticancer agents. In the present investigation, [...] Read more.
The Wnt signaling pathway is reported to be associated with lung cancer progression, metastasis and drug resistance, and thus it is an important therapeutic target for lung cancer. Plants have been shown as reservoirs of multiple potential anticancer agents. In the present investigation, the ethanolic leaf extract of Artemisia vulgaris (AvL-EtOH) was initially analyzed by means of gas chromatography-mass spectrometry (GC–MS) to identify the important phytochemical constituents. The GC–MS analysis of AvL-EtOH exhibited 48 peaks of various secondary metabolites such as terpenoids, flavonoids, carbohydrates, coumarins, amino acids, steroids, proteins, phytosterols, and diterpenes. It was found that the treatment with increasing doses of AvL-EtOH suppressed the proliferation and migration of lung cancer cells. Furthermore, AvL-EtOH induced prominent nuclear alteration along with a reduction in mitochondrial membrane potential and increased ROS (reactive oxygen species) generation in lung cancer cells. Moreover, AvL-EtOH-treated cells exhibited increased apoptosis, demonstrated by the activation of caspase cascade. AvL-EtOH also induced downregulation of Wnt3 and β-catenin expression along with cell cycle protein cyclin D1. Thus, the results of our study elucidated the potential of bioactive components of Artemisia vulgaris in the therapeutic management of lung cancer cells. Full article
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16 pages, 10176 KiB  
Article
Enhanced Antioxidant and Anticancer Potential of Artemisia carvifolia Buch Transformed with rol A Gene
by Amna Naheed Khan and Erum Dilshad
Metabolites 2023, 13(3), 351; https://doi.org/10.3390/metabo13030351 - 27 Feb 2023
Cited by 5 | Viewed by 1525
Abstract
Secondary metabolites have been shown to possess a range of biological functions. Flavonoids, due to their ability to scavenge ROS, are famous antioxidants. The plants of Artemisia species are rich sources of flavonoids; however, the amount of these metabolites is less. In the [...] Read more.
Secondary metabolites have been shown to possess a range of biological functions. Flavonoids, due to their ability to scavenge ROS, are famous antioxidants. The plants of Artemisia species are rich sources of flavonoids; however, the amount of these metabolites is less. In the current study, the flavonoid content was detected and then enhanced by genetically modifying the Artemisia carvifolia Buch with Agrobacterium tumefaciens strain GV3101 carrying rol A gene. The transformation of rol A gene was confirmed with PCR and the gene copy number was confirmed by Southern blot analysis. The HPLC analysis revealed the presence of catechin (3.19 ug/mg DW) and geutisic acid (2.22 ug/mg DW) in transformed plants, unlike wild-type plants. In transformed plants, all detected flavonoids (vanillic acid, rutin, catechine, gallic acid, syringic acid, caffeic acid, coumaric acid, geutisic acid, ferulic acid, and cinnamic acid) were increased up to several folds. Real-time qPCR revealed the higher expression levels of the genes for flavonoid biosynthesis enzymes phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS) in plants transformed with rol A genes, as the expression levels were increased up to 9–20-fold and 2–6-fold, respectively. The rol A transgenic lines T3 and T5 carrying two copies of rol A gene, particularly showed higher expression of both PAL and CHS gene, with the highest expression in T3 line. The transgenic lines demonstrated an average increase of 1.4-fold in the total phenolic content and 1–2-fold in the total flavonoid content as compared to wild-type plants. Total antioxidant capacity and total reducing power were increased up to an average of 1–2-fold and 1.5–2-fold respectively, along with increased free radical scavenging ability. Furthermore, the rol A gene transgenics were found to have much greater cytotoxic capacity than the A. carvifolia wild-type plant against the MCF7, HeLA, and HePG2 cancer cell lines. Current findings show that the rol A gene effectively increases the flavonoid content of A. carvifolia Buch, boosting the plant’s capacity as an antioxidant and an anticancer. This is the first-ever report, demonstrating the genetic transformation of Artemisia carvifolia Buch with rol A gene. Full article
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19 pages, 5524 KiB  
Article
Chemodiversity and Anti-Leukemia Effect of Metabolites from Penicillium setosum CMLD 18
by Ana Calheiros de Carvalho, Cauê Santos Lima, Heron Fernandes Vieira Torquato, André Tarsis Domiciano, Sebastião da Cruz Silva, Lucas Magalhães de Abreu, Miriam Uemi, Edgar Julian Paredes-Gamero, Paulo Cezar Vieira, Thiago André Moura Veiga and Lívia Soman de Medeiros
Metabolites 2023, 13(1), 23; https://doi.org/10.3390/metabo13010023 - 23 Dec 2022
Cited by 1 | Viewed by 1939
Abstract
Penicillium setosum represents a Penicillium species recently described, with little up-to-date information about its metabolic and biological potential. Due to this scenario, we performed chemical and biological studies of P. setosum CMLD18, a strain isolated from Swinglea glutinosa (Rutaceae). HRMS-MS guided dereplication strategies [...] Read more.
Penicillium setosum represents a Penicillium species recently described, with little up-to-date information about its metabolic and biological potential. Due to this scenario, we performed chemical and biological studies of P. setosum CMLD18, a strain isolated from Swinglea glutinosa (Rutaceae). HRMS-MS guided dereplication strategies and anti-leukemia assays conducted the isolation and characterization of six compounds after several chromatographic procedures: 2-chloroemodic acid (2), 2-chloro-1,3,8-trihydroxy-6- (hydroxymethyl)-anthraquinone (7), 7-chloroemodin (8), bisdethiobis(methylthio)acetylaranotine (9), fellutanine C (10), and 4-methyl-5,6-diihydro-2H-pyran-2-one (15). From the assayed metabolites, (10) induced cellular death against Kasumi-1, a human leukemia cell line, as well as good selectivity for it, displaying promising cytotoxic activity. Here, the correct NMR signal assignments for (9) are also described. Therefore, this work highlights more detailed knowledge about the P. setosum chemical profile as well as its biological potential, offering prospects for obtaining natural products with anti-leukemia capabilities. Full article
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Review

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30 pages, 3632 KiB  
Review
Evolution of Natural Product Scaffolds as Potential Proteasome Inhibitors in Developing Cancer Therapeutics
by Reyaz Hassan Mir, Prince Ahad Mir, Jasreen Uppal, Apporva Chawla, Mitesh Patel, Fevzi Bardakci, Mohd Adnan and Roohi Mohi-ud-din
Metabolites 2023, 13(4), 509; https://doi.org/10.3390/metabo13040509 - 31 Mar 2023
Cited by 3 | Viewed by 2019
Abstract
Homeostasis between protein synthesis and degradation is a critical biological function involving a lot of precise and intricate regulatory systems. The ubiquitin-proteasome pathway (UPP) is a large, multi-protease complex that degrades most intracellular proteins and accounts for about 80% of cellular protein degradation. [...] Read more.
Homeostasis between protein synthesis and degradation is a critical biological function involving a lot of precise and intricate regulatory systems. The ubiquitin-proteasome pathway (UPP) is a large, multi-protease complex that degrades most intracellular proteins and accounts for about 80% of cellular protein degradation. The proteasome, a massive multi-catalytic proteinase complex that plays a substantial role in protein processing, has been shown to have a wide range of catalytic activity and is at the center of this eukaryotic protein breakdown mechanism. As cancer cells overexpress proteins that induce cell proliferation, while blocking cell death pathways, UPP inhibition has been used as an anticancer therapy to change the balance between protein production and degradation towards cell death. Natural products have a long history of being used to prevent and treat various illnesses. Modern research has shown that the pharmacological actions of several natural products are involved in the engagement of UPP. Over the past few years, numerous natural compounds have been found that target the UPP pathway. These molecules could lead to the clinical development of novel and potent anticancer medications to combat the onslaught of adverse effects and resistance mechanisms caused by already approved proteasome inhibitors. In this review, we report the importance of UPP in anticancer therapy and the regulatory effects of diverse natural metabolites, their semi-synthetic analogs, and SAR studies on proteasome components, which may aid in discovering a new proteasome regulator for drug development and clinical applications. Full article
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