RESUMEN
The centrosome in animal cells is instrumental in spindle pole formation, nucleation, proper alignment of microtubules during cell division, and distribution of chromosomes in each daughter cell. Centrosome amplification involving structural and numerical abnormalities in the centrosome can cause chromosomal instability and dysregulation of the cell cycle, leading to cancer development and metastasis. However, disturbances caused by centrosome amplification can also limit cancer cell survival by activating mitotic checkpoints and promoting mitotic catastrophe. As a smart escape, cancer cells cluster their surplus of centrosomes into pseudo-bipolar spindles and progress through the cell cycle. This phenomenon, known as centrosome clustering (CC), involves many proteins and has garnered considerable attention as a specific cancer cell-targeting weapon. The kinesin-14 motor protein KIFC1 is a minus end-directed motor protein that is involved in CC. Because KIFC1 is upregulated in various cancers and modulates oncogenic signaling cascades, it has emerged as a potential chemotherapeutic target. Many molecules have been identified as KIFC1 inhibitors because of their centrosome declustering activity in cancer cells. Despite the ever-increasing literature in this field, there have been few efforts to review the progress. The current review aims to collate and present an in-depth analysis of known KIFC1 inhibitors and their biological activities. Additionally, we present computational docking data of putative KIFC1 inhibitors with their binding sites and binding affinities. This first-of-kind comparative analysis involving experimental biology, chemistry, and computational docking of different KIFC1 inhibitors may help guide decision-making in the selection and design of potent inhibitors.
Asunto(s)
Benchmarking , Neoplasias , Animales , Neoplasias/patología , Centrosoma/metabolismo , Sitios de Unión , MicrotúbulosRESUMEN
Centrosome amplification (CA) has been implicated in the progression of various cancer types. Although studies have shown that overexpression of PLK4 promotes CA, the effect of tumor microenvironment on polo-like kinase 4 (PLK4) regulation is understudied. The aim of this study was to examine the role of hypoxia in promoting CA via PLK4. We found that hypoxia induced CA via hypoxia-inducible factor-1α (HIF1α). We quantified the prevalence of CA in tumor cell lines and tissue sections from breast cancer, pancreatic ductal adenocarcinoma (PDAC), colorectal cancer, and prostate cancer and found that CA was prevalent in cells with increased HIF1α levels under normoxic conditions. HIF1α levels were correlated with the extent of CA and PLK4 expression in clinical samples. We analyzed the correlation between PLK4 and HIF1A mRNA levels in The Cancer Genome Atlas (TCGA) datasets to evaluate the role of PLK4 and HIF1α in breast cancer and PDAC prognosis. High HIF1A and PLK4 levels in patients with breast cancer and PDAC were associated with poor overall survival. We confirmed PLK4 as a transcriptional target of HIF1α and demonstrated that in PLK4 knockdown cells, hypoxia-mimicking agents did not affect CA and expression of CA-associated proteins, underscoring the necessity of PLK4 in HIF1α-related CA. To further dissect the HIF1α-PLK4 interplay, we used HIF1α-deficient cells overexpressing PLK4 and showed a significant increase in CA compared with HIF1α-deficient cells harboring wild-type PLK4. These findings suggest that HIF1α induces CA by directly upregulating PLK4 and could help us risk-stratify patients and design new therapies for CA-rich cancers. IMPLICATIONS: Hypoxia drives CA in cancer cells by regulating expression of PLK4, uncovering a novel HIF1α/PLK4 axis.
Asunto(s)
Carcinoma Ductal Pancreático , Centrosoma , Subunidad alfa del Factor 1 Inducible por Hipoxia , Neoplasias Pancreáticas , Proteínas Serina-Treonina Quinasas , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Hipoxia de la Célula , Línea Celular Tumoral , Centrosoma/metabolismo , Inducción Enzimática , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/genética , Microambiente TumoralRESUMEN
BACKGROUND: Psoriasis is a chronic inflammatory dermatological disorder having complex pathophysiology with autoimmune and genetic factors being the major players. Despite the availability of a gamut of therapeutic strategies, systemic toxicity, poor efficacy, and treatment tolerance due to genetic variability among patients remain the major challenges. This calls for effective intervention with the superior pharmacological profile. Nimbolide (NIM), a major limonoid is an active chemical constituent found in the leaves of the Indian Neem tree, Azadirachta indica. It has gained immense limelight in the past decades for the treatment of various diseases owing to its anti-proliferative, anti-inflammatory, and anti-cancer potentials. OBJECTIVE: The present study was centered around evaluating the anti-psoriatic effect of NIM in the experimental model of Imiquimod (IMQ)-induced psoriasis-like inflammation model. MATERIALS AND METHODS: Application of IMQ topically on the dorsum of Balb/c mice from day 0-6 prompted psoriasis-like inflammatory symptoms. Treatment groups included topical administration of NIM incorporated carbopol gel formulation and NIM free drug given through subcutaneous route. Protein expression studies such as immunohistochemistry, Western blotting, and ELISA were employed. RESULTS: It was clearly observed from our results that NIM significantly ameliorated the expression of inflammatory and proliferation mediators. Further, NIM in the treatment groups significantly improved classic Psoriasis Area Severity Index scoring when compared to IMQ administered group. CONCLUSION: It is noteworthy that NIM showed a predominant therapeutic effect as compared to other treatment group. To recapitulate, NIM has shown promising activity as an anti-psoriatic agent by remarkably ameliorating inflammation and associated proliferation.
Asunto(s)
Productos Biológicos/administración & dosificación , Imiquimod/efectos adversos , Limoninas/administración & dosificación , Psoriasis/tratamiento farmacológico , Administración Tópica , Animales , Modelos Animales de Enfermedad , Molécula 1 de Adhesión Intercelular/fisiología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/fisiología , Psoriasis/inducido químicamente , Índice de Severidad de la EnfermedadRESUMEN
With increasing global cases and mortality rates due to COVID-19 infection, finding effective therapeutic interventions has become a top priority. Marine resources are not explored much and to be taken into consideration for exploring antiviral potential. Chitosan (carbohydrate polymer) is one such bioactive glycan found ubiquitously in marine organisms. The presence of reactive amine/hydroxyl groups, with low toxicity/allergenicity, compels us to explore it against SARS-CoV-2. We have screened a library of chitosan derivatives by site-specific docking at not only spike protein Receptor Binding Domain (RBD) of wild type SARS-CoV-2 but also on RBD of B.1.1.7 (UK) and P.1 (Brazil) SARS-CoV-2 variants. The obtained result was very interesting and ranks N-benzyl-O-acetyl-chitosan, Imino-chitosan, Sulfated-chitosan oligosaccharides derivatives as a potent antiviral candidate due to its high binding affinity of the ligands (-6.0 to -6.6 kcal/mol) with SARS-CoV-2 spike protein RBD and they critically interacting with amino acid residues Tyr 449, Asn 501, Tyr 501, Gln 493, Gln 498 and some other site-specific residues associated with higher transmissibility and severe infection. Further ADMET analysis was done and found significant for exploration of the future therapeutic potential of these three ligands. The obtained results are highly encouraging in support for consideration and exploration in further clinical studies of these chitosan derivatives as anti-SARS-CoV-2 therapeutics.
Asunto(s)
Antivirales/farmacología , Quitosano/farmacología , Variación Genética , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Antivirales/química , Sitios de Unión , Brasil , Quitosano/química , Modelos Moleculares , Simulación del Acoplamiento Molecular , Unión Proteica , Conformación Proteica/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Reino Unido , Internalización del Virus/efectos de los fármacosRESUMEN
Chitosan is a deacetylated polycationic polysaccharide derived from chitin. It is structurally constituted of N-acetyl-D-glucosamine and ß-(1-4)-linked D-glucosamine where acetyl groups are randomly distributed across the polymer. The parameters of deacetylation and depolymerization process greatly influence various physico-chemical properties of chitosan and thus, offer a great degree of manipulation to synthesize chitosan of interest for various industrial and biomedical applications. Chitosan and its various derivatives have been a potential molecule of investigation in the area of anti-microbials especially anti-fungal, anti-bacterial and antiviral. The current review predominantly highlights and discusses about the antiviral activities of chitosan and its various substituted derivatives against a wide spectrum of human, animal, plants and bacteriophage viruses. The extrinsic and intrinsic factors that affect antiviral efficacy of chitosan have also been talked about. With the rapid unfolding of COVID-19 pandemic across the globe, we look for chitosan as a plausible potent antiviral molecule for fighting this disease. Through this review, we present enough literature data supporting role of chitosan against different strains of SARS viruses and also chitosan targeting CD147 receptors, a novel route for invasion of SARS-CoV-2 into host cells. We speculate the possibility of using chitosan as potential molecule against SARS-CoV-2 virus.