RESUMEN
Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial in the metastatic cascade. Among these, super-enhancers (SEs), emerging as new epigenetic regulators, consist of large clusters of regulatory elements that drive the high-level expression of genes essential for the oncogenic process, upon which cancer cells develop a profound dependency. These SE-driven oncogenes play an important role in regulating various facets of metastasis, including the promotion of tumor proliferation in primary and distal metastatic organs, facilitating cellular migration and invasion into the vasculature, triggering epithelial-mesenchymal transition, enhancing cancer stem cell-like properties, circumventing immune detection, and adapting to the heterogeneity of metastatic niches. This heavy reliance on SE-mediated transcription delineates a vulnerable target for therapeutic intervention in cancer cells. In this article, we review current insights into the characteristics, identification methodologies, formation, and activation mechanisms of SEs. We also elaborate the oncogenic roles and regulatory functions of SEs in the context of cancer metastasis. Ultimately, we discuss the potential of SEs as novel therapeutic targets and their implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.
Asunto(s)
Elementos de Facilitación Genéticos , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Neoplasias , Humanos , Neoplasias/patología , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Animales , Epigénesis Genética , Terapia Molecular Dirigida , Transición Epitelial-MesenquimalRESUMEN
Sanguinarine is a quaternary ammonium benzophenanthine alkaloid found in traditional herbs such as Chelidonium, Corydalis, Sanguinarum, and Borovula. It has been proven to possess broad-spectrum biological activities, such as antitumor, anti-inflammatory, antiosteoporosis, neuroprotective, and antipathogenic microorganism activities. In this paper, recent progress on the biological activity and mechanism of action of sanguinarine and its derivatives over the past ten years is reviewed. The results showed that the biological activities of hematarginine and its derivatives are related mainly to the JAK/STAT, PI3K/Akt/mTOR, NF-κB, TGF-ß, MAPK and Wnt/ß-catenin signaling pathways. The limitations of using sanguinarine in clinical application are also discussed, and the research prospects of this subject are outlined. In general, sanguinarine, a natural medicine, has many pharmacological effects, but its toxicity and safety in clinical application still need to be further studied. This review provides useful information for the development of sanguinarine-based bioactive agents.
Asunto(s)
Alcaloides , Fosfatidilinositol 3-Quinasas , Fosfatidilinositol 3-Quinasas/metabolismo , Benzofenantridinas/farmacología , Alcaloides/metabolismo , Isoquinolinas/farmacologíaRESUMEN
Currently, natural products are one of the priceless options for finding novel chemical pharmaceutical entities. Ellipticine is a naturally occurring alkaloid isolated from the leaves of Ochrosia elliptica Labill. Ellipticine and its derivatives are characterized by multiple biological activities. The purpose of this review was to provide a critical and systematic assessment of ellipticine and its derivatives as bioactive molecules over the last 60â years. Publications focused mainly on the total synthesis of alkaloids of this type without any evaluation of bioactivity have been excluded. We have reviewed papers dealing with the synthesis, bioactivity evaluation and mechanism of action of ellipticine and its derivatives. It was found that ellipticine and its derivatives showed cytotoxicity, antimicrobial ability, and anti-inflammatory activity, among which cytotoxicity toward cancer cell lines was the most investigated aspect. The inhibition of DNA topoisomerase II was the most relevant mechanism for cytotoxicity. The PI3K/AKT pathway, p53 pathway, and MAPK pathway were also closely related to the antiproliferative ability of these compounds. In addition, the structure-activity relationship was deduced, and future prospects were outlined. We are confident that these findings will lay a scientific foundation for ellipticine-based drug development, especially for anticancer agents.
Asunto(s)
Elipticinas , Elipticinas/farmacología , Elipticinas/química , Humanos , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinfecciosos/farmacología , Antiinfecciosos/química , Estructura Molecular , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificaciónRESUMEN
Sinomenine, an isoquinoline alkaloid extracted from the roots and stems of Sinomenium acutum, has been extensively studied for its derivatives as bioactive agents. This review concentrates on the research advancements in the biological activities and action mechanisms of sinomenine-related compounds until November 2023. The findings indicate a broad spectrum of pharmacological effects, including antitumor, anti-inflammation, neuroprotection, and immunosuppressive properties. These compounds are notably effective against breast, lung, liver, and prostate cancers, exhibiting IC50 values of approximately 121.4 nM against PC-3 and DU-145 cells, primarily through the PI3K/Akt/mTOR, NF-κB, MAPK, and JAK/STAT signaling pathways. Additionally, they manifest anti-inflammatory and analgesic effects predominantly via the NF-κB, MAPK, and Nrf2 signaling pathways. Utilized in treating rheumatic arthritis, these alkaloids also play a significant role in cardiovascular and cerebrovascular protection, as well as organ protection through the NF-κB, Nrf2, MAPK, and PI3K/Akt/mTOR signaling pathways. This review concludes with perspectives and insights on this topic, highlighting the potential of sinomenine-related compounds in clinical applications and the development of medications derived from natural products.
Asunto(s)
Alcaloides , Morfinanos , Masculino , Humanos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt , Factor 2 Relacionado con NF-E2 , Fosfatidilinositol 3-Quinasas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Morfinanos/farmacología , Serina-Treonina Quinasas TOR , Alcaloides/farmacologíaRESUMEN
Natural products are treasure houses for modern drug discovery. Diphyllin is a natural arylnaphthalene lignan lactone isolated from the leaf of Astilboides tabularis. Studies have found that it possesses plenty of bioactivity characteristics. In this paper, we reviewed the structure, bioactivity, and mechanism of action of diphyllin and its derivatives. The references were obtained from PubMed, Web of Science, and Science Direct databases up to August 2023. Papers without a bio-evaluation were excluded. Diphyllin and its derivatives have demonstrated V-ATPase inhibition, anti-tumor, anti-virus, anti-biofilm, anti-inflammatory, and anti-oxidant activities. The most studied activities of diphyllin and its derivatives are V-ATPase inhibition, anti-tumor activities, and anti-virus activities. Furthermore, V-ATPase inhibition activity is the mechanism of many bioactivities, including anti-tumor, anti-virus, and anti-inflammatory activities. We also found that the galactosylated modification of diphyllin is a common phenomenon in plants, and therefore, galactosylated modification is applied by researchers in the laboratory to obtain more excellent diphyllin derivatives. This review will provide useful information for the development of diphyllin-based anti-tumor and anti-virus compounds.
Asunto(s)
Lignanos , Adenosina Trifosfatasas , Antiinflamatorios/farmacología , Lactonas , Lignanos/farmacología , Lignanos/químicaRESUMEN
Heterocycles are common in the structure of drugs used clinically to deal with diseases. Such drugs usually contain nitrogen, oxygen and sulfur, which possess electron-accepting capacity and can form hydrogen bonds. These properties often bring enhanced target binding ability to these compounds when compared to alkanes. Pyrazine is a nitrogen-containing six-membered heterocyclic ring and many of its derivatives are identified as bioactive molecules. We review here the most active pyrazine compounds in terms of their structure, activity in vitro and in vivo (mainly antitumor activity) and the reported mechanisms of action. References have been downloaded through Web of Science, PubMed, Science Direct, Google Scholar and SciFinder Scholar. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. We found that compounds in which a pyrazine ring was fused into other heterocycles especially pyrrole or imidazole were the highly studied pyrazine derivatives, whose antineoplastic activity had been widely investigated. To the best of our knowledge, this is the first review of pyrazine derivatives and their bioactivity, especially their antitumor activity. This review should be useful for those engaged in development of medications based on heterocyclic compounds especially those based on pyrazine.
Asunto(s)
Antineoplásicos , Compuestos Heterocíclicos , Pirazinas/farmacología , Pirazinas/química , Compuestos Heterocíclicos/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , NitrógenoRESUMEN
Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.
Asunto(s)
Alcaloides , Antineoplásicos , Compuestos Heterocíclicos de Anillo en Puente , Neoplasias , Humanos , Antineoplásicos/farmacología , Azepinas/farmacología , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Lactonas/farmacología , Apoptosis , Alcaloides/farmacología , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular TumoralRESUMEN
Securinega alkaloids are indolizidine alkaloids extracted from the leaf and root of an Asian plant, Securinega suffruticosa. Since its discovery in 1956 by Russian scientists, numerous studies have been conducted on securinega alkaloids and their derivatives as bioactive agents. In this review, published work on the bioactivities and the mechanism of action of securinega alkaloids and their derivatives is addressed. References were obtained through for example, the Web of Science, Science Direct, Pubmed and Google Scholar. Research into the synthesis of securinega alkaloids and their derivatives lacking activity assessment has been excluded. Comprehensive reviews show that securinega alkaloids and their derivatives exhibit a wide range of activities among which antineoplastic activity and nervous system related activity were reported although the mechanisms of action remain in part unknown. The other activities such as induction of differentiation, reversal of multi-drug resistance, cardiovascular system related activity, anti-inflammatory, adjuvant agent and anti-pathogenic activity are also reviewed. We found that modification at the C12, C14, and C15 sites on securinine improves the antitumor activity, while derivatives in which a bivalent mimetic is linked to the C15 site is beneficial for differentiation induction activity and reversal of P-glycoprotein mediated drug resistance. The most related pathways involved in the bioactivity of securinega alkaloids and their derivatives are JAK/STAT, PI3K/AKT/mTOR and MAPK. A perspective and expectation concerning the research of securinega alkaloids is presented at the end of this article. This review indicates directions around which constant endeavor could be valuable for researchers in the near future.