scholarly journals CDK9: A Comprehensive Review of Its Biology, and Its Role as a Potential Target for Anti-Cancer Agents

2021 ◽  
Vol 11 ◽  
Author(s):  
Abel Tesfaye Anshabo ◽  
Robert Milne ◽  
Shudong Wang ◽  
Hugo Albrecht

Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.

2018 ◽  
Vol 13 (3) ◽  
pp. 203 ◽  
Author(s):  
Maria Javeed ◽  
Azhar Rasul ◽  
Ghulam Hussain ◽  
Farhat Jabeen ◽  
Bilal Rasool ◽  
...  

<p>This review article aims to provide an update on the sources, pharmaco-logical and biological profile of a β-carboline alkaloid, harmine which is a major bioactive component of various plants mainly Peganum harmala. Harmine’s wide range of pharmacological properties has been well-documented as anti-cancer, anti-inflammatory, anti-oxidant, neuroprotective, anti-depressant, and antimicrobial. Although reported data suggests a multifunctional pharmacological role of harmine but farther experimentation on its molecular mechanism of action, synthetic chemistry approaches, and preclinical studies are yet obligatory to fully uncover its pharmacological efficacy.</p>


2020 ◽  
Vol 20 (12) ◽  
pp. 1074-1092 ◽  
Author(s):  
Rammohan R.Y. Bheemanaboina

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.


2021 ◽  
Vol 22 (7) ◽  
pp. 3755
Author(s):  
Jakub Rok ◽  
Zuzanna Rzepka ◽  
Justyna Kowalska ◽  
Klaudia Banach ◽  
Artur Beberok ◽  
...  

Minocycline is a drug which induces skin hyperpigmentation. Its frequency reaches up to 50% of treated patients. The adverse effect diminishes the great therapeutic potential of minocycline, including antibacterial, neuroprotective, anti-inflammatory and anti-cancer actions. It is supposed that an elevated melanin level and drug accumulation in melanin-containing cells are related to skin hyperpigmentation. This study aimed to evaluate molecular and biochemical mechanism of minocycline-induced hyperpigmentation in human normal melanocytes, as well as the contribution of UV radiation to this side effect. The experiments involved the evaluation of cyto- and phototoxic potential of the drug using cell imaging with light and confocal microscopes as well as biochemical and molecular analysis of melanogenesis. We showed that minocycline induced melanin synthesis in epidermal melanocytes. The action was intensified by UV irradiation, especially with the UVB spectrum. Minocycline stimulated the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) gene. Higher levels of melanin and increased activity of tyrosinase were also observed in treated cells. Moreover, minocycline triggered the supranuclear accumulation of tyrosinase, similar to UV radiation. The decreased level of premelanosome protein PMEL17 observed in all minocycline-treated cultures suggests disorder of the formation, maturation or distribution of melanosomes. The study revealed that minocycline itself was able to enhance melanin synthesis. The action was intensified by irradiation, especially with the UVB spectrum. Demonstrated results confirmed the potential role of melanin and UV radiation minocycline-induced skin hyperpigmentation.


Author(s):  
Emdormi Rymbai ◽  

Plants are an important source of natural products and they play a vital role in the field of medicinal chemistry and pharmaceutical science. Traditional medicines have been practiced and used for thousands of years, mostly in Asian countries, where plants are the main sources of medicine. Houttuynia cordata, a herb that belongs to the family Saururaceae, has a wide range of pharmacological activities and is used traditionally in conditions like anisolobis sores, heatstroke, lung carbuncles, malaria, scrotal abscess, tonsillitis, salammoniac poison and has also been widely accepted to possess anti-cancer, anti-oxidant, anti-hypertension, anti-inflammatory, anti-mutagenic, antibacterial, anti-viral and anti-purulent activity. Moreover, it is one of the herbs that was recognized during pandemic outbreaks, such as Severe Acute Respiratory Syndrome Coronavirus (SARS CoV) in China, virulent Newcastle Disease Virus (VNDV) in Java (Indonesia) and Newcastle (England). In this review, we briefly discuss the role of H. cordata as an anti-viral agent and the possibility of developing a dosage form against Coronavirus disease-19 (COVID-19).


2018 ◽  
Vol 19 (10) ◽  
pp. 3219 ◽  
Author(s):  
Balbina García-Reyes ◽  
Anna-Laura Kretz ◽  
Jan-Philipp Ruff ◽  
Silvia von Karstedt ◽  
Andreas Hillenbrand ◽  
...  

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC’s resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.


2020 ◽  
Vol 75 (3) ◽  
pp. 477-491
Author(s):  
Kiss Mariann ◽  
Németh Dezső ◽  
Janacsek Karolina

A hétköznapok során gyakran előfordul, hogy gyengén teljesítünk egy olyan helyzetben, amelyben korábban már bizonyítottuk tudásunkat. A pszichológián belül elméleti és empirikus eredmények is alátámasztják ezt a hétköznapi jelenséget, mely szerint egy adott időpontban mérhető teljesítmény (performancia) nem feltétlenül tükrözi hűen a mögötte álló tudást (kompetencia). Jelen rövid, célzott összefoglaló tanulmánnyal az a célunk, hogy felhívjuk a fi gyelmet a performancia-kompetencia disszociációra a procedurális tanulás területét használva példaként. Fontos azonban kiemelni, hogy ez a jelenség más kognitív funkciók esetén is jelen lehet (pl. nyelvi teljesítmény, döntéshozatal, észlelés), ezért tanulmányunk új kutatásokat ösztönözhet számos kognitív funkció esetén. A korábbi empirikus eredmények áttekintésekor külön hangsúlyt fektetünk a tanulás idői faktoraira, amelyek meghatározhatják, hogy disszociáció lép-e fel adott esetben a performancia és kompetencia között vagy nem. Ezután kitérünk azokra az elméleti magyarázatokra is, amelyek az idői faktorok tanulásra, illetve performancia-kompetencia disszociációra kifejtett hatását próbálják magyarázni. A tanulmány végén kitekintést nyújtunk a disszociáció kutatásmódszertani vonatkozásaira és olyan alkalmazott helyzetekre is, ahol ez a disszociáció jelentősen befolyásolhatja a levont következtetéseket: ilyen például az oktatási-tanulási környezet (készségtanulás, nyelvtanulás), illetve a kognitív tesztek használata a klinikai diagnosztikában. It often occurs in our daily life that we perform weaker in a task in which we have previously shown good knowledge and understanding. In psychology, both theoretical and empirical evidence supports this phenomenon: that is, on certain occasions, our momentary performance does not accurately refl ect our underlying knowledge (competence). The aim of our short, focused review paper is to draw attention to this performance vs. competence dissociation using the fi eld of procedural learning as an example. It is important to note, however, that this phenomenon may occur for a wide range of cognitive functions (e.g., aspects of language performance, decision-making, perception), and therefore, our paper can stimulate research in these areas. In this paper, we review previous empirical fi ndings that focused on the role of temporal factors in procedural learning as these factors can affect whether or not dissociation occurs in a certain case. Then, we briefl y present the explanatory accounts of the role of the temporal factors in learning and in performance vs. competence dissociation. Finally, our review discusses the implications of the presented fi ndings both from a methodological and an applied perspective, highlighting that the dissociation between performance and competence can substantially alter the outcomes and our interpretations in various situations such as in education (e.g., skill learning, language learning) and when applying cognitive tests in clinical settings.


Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1586
Author(s):  
Salinee Jantrapirom ◽  
Luca Lo Piccolo ◽  
Dumnoensun Pruksakorn ◽  
Saranyapin Potikanond ◽  
Wutigri Nimlamool

Ubiquilins or UBQLNs, members of the ubiquitin-like and ubiquitin-associated domain (UBL-UBA) protein family, serve as adaptors to coordinate the degradation of specific substrates via both proteasome and autophagy pathways. The UBQLN substrates reveal great diversity and impact a wide range of cellular functions. For decades, researchers have been attempting to uncover a puzzle and understand the role of UBQLNs in human cancers, particularly in the modulation of oncogene’s stability and nucleotide excision repair. In this review, we summarize the UBQLNs’ genetic variants that are associated with the most common cancers and also discuss their reliability as a prognostic marker. Moreover, we provide an overview of the UBQLNs networks that are relevant to cancers in different ways, including cell cycle, apoptosis, epithelial-mesenchymal transition, DNA repairs and miRNAs. Finally, we include a future prospective on novel ubiquilin-based cancer therapies.


2013 ◽  
Vol 41 (1) ◽  
pp. 293-298 ◽  
Author(s):  
Samireh Jorfi ◽  
Jameel M. Inal

Microvesicles are shed constitutively, or upon activation, from both normal and malignant cells. The process is dependent on an increase in cytosolic Ca2+, which activates different enzymes, resulting in depolymerization of the actin cytoskeleton and release of the vesicles. Drug resistance can be defined as the ability of cancer cells to survive exposure to a wide range of anti-cancer drugs, and anti-tumour chemotherapeutic treatments are often impaired by innate or acquired MDR (multidrug resistance). Microvesicles released upon chemotherapeutic agents prevent the drugs from reaching their targets and also mediate intercellular transport of MDR proteins.


2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.


2015 ◽  
Vol 308 (4) ◽  
pp. H259-H268 ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yun Chen ◽  
Mitsuaki Isobe ◽  
Åsa B. Gustafsson ◽  
Richard N. Kitsis ◽  
...  

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.


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