RESUMO
Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.
Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Animais , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Camundongos , Linhagem Celular Tumoral , Antimitóticos/farmacologia , Antimitóticos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , MasculinoRESUMO
BACKGROUND: Plantar warts are common infectious cutaneous growths causing severe physiological and psychological discomforts in patients and heaving global financial burdens. However, paucity of clear-cut guidelines for plantar warts, selecting appropriate treatments for plantar warts remains challenging. The objective of the study is to evaluate the efficacy and safety of common treatments for plantar warts. METHODS: PubMed, EMbase, and The Cochrane Library were searched from inception to March 1, 2023 for randomized controlled trials (RCTs) of plantar warts. The primary outcome (complete response) and secondary outcome (recurrence and pain) were extracted and combined using Bayesian network meta-analysis (NMA) with random-effect and fixed-effect models. RESULTS: Totally, 33 RCTs were included in the systematic review and quantitative NMA. In NMA of complete response, topical application of 1% cantharidin, 20% podophylotoxin, 30% salicylic acid (CPS), microneedles plus bleomycin (MNB), and intralesional bleomycin injection (INB) were the only three treatments significantly superior to no treatment (NT) and CPS was of the highest possibility to be the top-ranked treatment (SUCRA = 0.9363). However, traditional warts treatments, salicylic acid (SA) and cryotherapy were not superior to NT. CONCLUSIONS: The NMA has produced evidence for using CPS, MNB, and INB, which are all topical antimitotic treatments, to improve the management of plantar warts. The classic treatment modalities for plantar warts, including SA and cryotherapy, may play a less important role in the clinical practice of plantar warts.
Assuntos
Teorema de Bayes , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Verrugas , Humanos , Verrugas/tratamento farmacológico , Antimitóticos/uso terapêutico , Antimitóticos/administração & dosagem , Ácido Salicílico/uso terapêutico , Ácido Salicílico/administração & dosagem , Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Podofilotoxina/uso terapêutico , Podofilotoxina/administração & dosagem , Cantaridina/uso terapêutico , Cantaridina/administração & dosagem , Administração TópicaRESUMO
The cell cycle is a highly regulated and orchestrated mechanism of life that ensures successive division of a cell and precise replication of cellular contents. Cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors are three of the most critical cell cycle regulatory proteins that enable the smooth progression of cells through the different phases of cell cycle before and after division. The alteration of cell cycle-related proteins causes aberration in the normal cell cycle process, which is one of the pivotal causes of cancer and other diseases. Targeting cell cycle components has proven to be a valuable therapeutic strategy and leads to the development of novel anticancer therapeutic. The purpose of this book chapter is to summarize the literature and discuss the clinical significance of cell cycle-related proteins in cancers and other diseases, with a focus on identifying potential targets as therapeutic interventions for cancer patients.
Assuntos
Antimitóticos , Proteínas de Ciclo Celular , Ciclo Celular , Quinases Ciclina-Dependentes , Neoplasias , Antimitóticos/uso terapêutico , Divisão Celular , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismoRESUMO
Albendazole is considered the anthelmintic of choice for the management of rat lungworm disease (neuroangiostrongyliasis), due to its broad spectrum of nematocidal activity and its ability to cross the blood-brain barrier. Albendazole binds to ß-tubulins, preventing their polymerization into microtubules, thereby corrupting the cascade of cell division at metaphase, which ultimately leads to the death of individual cells and eventually the death of the parasite. Inhibition of microtubule formation will also hinder the axoplasmic transport system, affecting the neuronal activities of the parasite. While this mechanism has been explicated in other parasitic and non-parasitic nematodes, it has never been evaluated in Angiostrongylus cantonensis. This study evaluates the antimitotic effects of albendazole sulphoxide (active metabolite) on the microtubules of adult A. cantonensis using the tubulin polymerization assay and measures its effects on worm viability using the colorimetric MTT assay. Three different concentrations of albendazole (62.5 µM, 250 µΜ, and 1 mM) were evaluated. We saw a statistically significant dose-dependent reduction in the band intensity of polymerized tubulins (or microtubules) (P = 0.019), suggesting that albendazole imparts its antimitotic effect in a dose-dependent manner. Similarly, our MTT assay showed a dose-dependent decrease in formazan intensity (proportional to cell viability), suggesting that the rate of nematocidal activity of albendazole is also proportional to its concentration. In compiling the results from both these experiments, a correlation between the microtubule assembly and worm viability is evident.
Assuntos
Angiostrongylus cantonensis , Anti-Helmínticos , Antimitóticos , Infecções por Strongylida , Animais , Ratos , Angiostrongylus cantonensis/fisiologia , Albendazol/farmacologia , Albendazol/uso terapêutico , Tubulina (Proteína) , Antimitóticos/farmacologia , Antimitóticos/uso terapêutico , Formazans , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Antinematódeos/farmacologia , Infecções por Strongylida/tratamento farmacológico , Infecções por Strongylida/parasitologiaRESUMO
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.
Assuntos
Antimitóticos , Antineoplásicos , Neoplasias , Alcaloides de Vinca , Antimitóticos/metabolismo , Antimitóticos/farmacologia , Antimitóticos/uso terapêutico , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Microtúbulos/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Alcaloides de Vinca/metabolismo , Alcaloides de Vinca/farmacologia , Alcaloides de Vinca/uso terapêuticoRESUMO
PURPOSE: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. METHODS AND MATERIALS: Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. RESULTS: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. CONCLUSIONS: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.
Assuntos
Antimitóticos , Neoplasias Encefálicas , Terapia por Estimulação Elétrica , Glioblastoma , Antimitóticos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Terapia por Estimulação Elétrica/métodos , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Humanos , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: The aim of this study was to screen plant extracts for antimitotic activity using Vigna radiata germination inhibition assay, followed by Allium cepa root tip assay and evaluation of their cytotoxic potential on colon carcinoma (HCT-116) cell lines. SUBJECTS AND METHODS: Aqueous extracts of Aconitum heterophyllum, Terminalia bellirica, Bauhinia variegata, Vanda roxburghii, and Cassia angustifolia were prepared by maceration method, and preliminary screening studies to check their antimitotic activity were done by V. radiata germination inhibition assay, followed by A. cepa root tip assay. Furthermore, cytotoxic actions were evaluated by cell proliferation assay. Effect of T. bellirica aqueous extract was analyzed to induce morphological changes, cell death, lactate dehydrogenase release, and cell survival of HCT-116 cells. STATISTICAL ANALYSIS USED: The data represented were analyzed by Student's t-test using SigmaStat 2.0 statistical analysis software. The normality of data was tested by the Shapiro-Wilk test before the Student's t-test. P values *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 were considered as statistically significant. RESULTS: All the plant extracts showed promising antimitotic activity. Out of all, T. bellirica was highly effective on HCT-116 cells and promising effect on cell proliferation assay and Annexin-propidium iodide staining revealed that T. bellirica efficiently induces apoptosis. CONCLUSIONS: T. bellirica inhibits cancer cell growth and induces apoptotic cell death. Collectively, it may hold potential for cancer therapeutics.
Assuntos
Antimitóticos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Extratos Vegetais/farmacologia , Aconitum/química , Antimitóticos/isolamento & purificação , Antimitóticos/uso terapêutico , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Bauhinia/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Orchidaceae/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Senna/química , Terminalia/químicaRESUMO
Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Terapia Combinada/métodos , Imunoterapia/métodos , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Alquilantes/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antimitóticos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Vírus Oncolíticos/imunologia , Compostos de Platina/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores da Topoisomerase/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
In this era of multi-drug resistance (MDR), antimicrobial peptides (AMPs) are one of the most promising classes of potential drug candidates to combat communicable as well as noncommunicable diseases such as cancers and diabetes. AMPs show a wide spectrum of biological activities which include antiviral, antifungal, anti-mitogenic, anticancer, and anti-inflammatory properties. Apart from these prospective therapeutic potentials, the AMPs can act as food preservatives and immune modulators. Therefore, AMPs have the potential to replace conventional drugs and may gain a significant global drug market share. Although several AMPs have shown therapeutic potential in vitro or in vivo, in most cases they have failed the clinical trial owing to various issues. In this review, we discuss in brief (i) molecular mechanisms of AMPs in various diseases, (ii) importance of AMPs in pharmaceutical industries, (iii) the challenges in using AMPs as therapeutics and how to overcome, (iv) available AMP therapeutics in market, and (v) AMPs under clinical trials. Here, we specifically focus on the therapeutic AMPs in the areas of dermatology, surgery, oncology and metabolic diseases.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antimitóticos/farmacologia , Antimitóticos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Conservantes de Alimentos/farmacologia , Conservantes de Alimentos/uso terapêutico , HumanosRESUMO
Arry-520 is an advanced drug candidate from the Eg5 inhibitor class undergoing clinical evaluation in patients with relapsed or refractory multiple myeloma. Here, we show by structural analysis that Arry-520 binds stoichiometrically to the motor domain of Eg5 in the conventional allosteric loop L5 pocket in a complex that suggests the same structural mechanism as other Eg5 inhibitors. We have previously shown that acquired resistance through mutations in the allosteric-binding site located at loop L5 in the Eg5 structure appears to be independent of the inhibitors' scaffold, which suggests that Arry-520 will ultimately have the same fate. When Arry-520 was assessed in two cell lines selected for the expression of either Eg5(D130A) or Eg5(L214A) STLC-resistant alleles, mutations previously shown to convey resistance to this class of inhibitors, it was inactive in both. Surprisingly, when the cells were challenged with ispinesib, another Eg5 inhibitor, the Eg5(D130A) cells were resistant, but those expressing Eg5(L214A) were strikingly sensitive. Molecular dynamics simulations suggest that subtle differences in ligand binding and flexibility in both compound and protein may alter allosteric transmission from the loop L5 site that do not necessarily result in reduced inhibitory activity in mutated Eg5 structures. Although we predict that cells challenged with Arry-520 in the clinical setting are likely to acquire resistance through point mutations in the Eg5-binding site, the data for ispinesib suggest that this resistance mechanism is not scaffold independent as previously thought, and new inhibitors can be designed that retain inhibitory activity in these resistant cells.
Assuntos
Antimitóticos/uso terapêutico , Tiadiazóis/uso terapêutico , Antimitóticos/farmacologia , Técnicas de Cultura de Células , Humanos , Modelos Moleculares , Tiadiazóis/farmacologiaRESUMO
Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.
Assuntos
Antimitóticos/uso terapêutico , Glioblastoma/tratamento farmacológico , Noscapina/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antimitóticos/farmacologia , Linhagem Celular Tumoral , Humanos , Mitose/efeitos dos fármacos , Noscapina/farmacologia , Moduladores de Tubulina/farmacologiaRESUMO
Cancers are one of the leading causes of deaths affecting millions of people around the world, therefore they are currently a major public health problem. The treatment of cancer is based on surgical resection, radiotherapy, chemotherapy or immunotherapy, much of which is often insufficient and cause serious, burdensome and undesirable side effects. For many years, assorted secondary metabolites derived from plants have been used as antitumor agents. Recently, researchers have discovered a large number of new natural substances which can effectively interfere with cancer cells' metabolism. The most famous groups of these compounds are topoisomerase and mitotic inhibitors. The aim of the latest research is to characterize natural compounds found in many common foods, especially by means of their abilities to regulate cell cycle, growth and differentiation, as well as epigenetic modulation. In this paper, we focus on a review of recent discoveries regarding nature-derived anticancer agents.
Assuntos
Antimitóticos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Dieta , Neoplasias/tratamento farmacológico , Inibidores da Topoisomerase/uso terapêutico , Animais , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologiaRESUMO
BACKGROUND: Eribulin has efficacy in patients with progression after ≥ 1 chemotherapeutic regimen for metastatic breast cancer (MBC). A short disease-free interval (DFI) and previous use of taxanes in the neoadjuvant or adjuvant setting have been associated with worse outcomes for patients receiving first-line chemotherapy for HER2-negative MBC. The aim of the present trial was to evaluate the efficacy and safety of eribulin as first-line therapy for patients with HER2-negative MBC with these poor prognostic factors. PATIENTS AND METHODS: Eribulin monotherapy was administered until disease progression or unacceptable toxicity. The principal selection criteria were HER2 negativity without previous chemotherapy for MBC, the previous use of taxanes for early-stage breast cancer, and a DFI of < 36 months (subsequently amended to 48 months). The primary endpoint was the investigator-assessed time to progression. The secondary endpoints included overall survival, progression-free survival, objective response rate, clinical benefit rate, duration of response, and toxicity profile. A total of 53 patients were enrolled and received ≥ 1 dose of eribulin. RESULTS: The median patient age was 47 years (range, 23-82.8 years). The median DFI was 15.7 months (range, 0.1-46.4 months). The median investigator-assessed time to progression was 4.1 months (range, 0.2-27.8 months; 95% confidence interval, 3.2-6.2 months). The objective response and clinical benefit rate was 20.8% and 26.4%, respectively. All-grade and grade 3/4 adverse events developed in 96.2% and 69.8% of patients, respectively. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and anemia. CONCLUSION: Eribulin is effective and safe as first-line therapy for aggressive taxane-pretreated HER2-negative MBC.
Assuntos
Antimitóticos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimitóticos/efeitos adversos , Antineoplásicos/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Furanos/efeitos adversos , Humanos , Cetonas/efeitos adversos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/metabolismo , Taxoides/farmacologia , Taxoides/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Clinicians struggle with limited efficacy and durability of standard treatments when treating patients with Dupuytren disease diathesis. Alternative treatments such as low-dose radiation therapy in early phase of disease, supplemental pharmacotherapy with anti-inflammatory and/or anti-mitotic drugs, as well as other pharmacologic targets, and more aggressive surgery such as dermofasciectomy all have been reported with variable success or with serious side effects that hamper their standard use. This article gives an overview of the available literature.
Assuntos
Contratura de Dupuytren/terapia , Derme Acelular , Anti-Inflamatórios/uso terapêutico , Antimitóticos/uso terapêutico , Fasciotomia/métodos , Humanos , Radioterapia , Prevenção Secundária , Retalhos CirúrgicosRESUMO
Circular RNAs (circRNAs), a class of endogenous RNAs, have emerged as an enigmatic class of genes. However, little is known about their value in the progression and chemoresistance of cancers. The present study sought to determine the expression profiles and potential modulatory role of circRNAs on breast cancer cell viability and monastrol resistance. Monastrol-resistant cell lines were established by exposing breast cancer cells to increasing concentrations of monastrol. A human circRNA microarray was used to search for dysregulated circRNAs in monastrol-resistant cells, then circRNAMTO1 (hsacircRNA-007874) was validated as a circRNA that exhibited elevated expression levels in monastrol-resistant cells. Mechanistic investigations suggested that upregulation of circRNAMTO1 suppressed cell viability, promoted monastrol-induced cell cytotoxicity and reversed monastrol resistance. Subsequently, Eg5 was identified as the functional target of circRNAMTO1, and MTO1 inhibited Eg5 protein level but not mRNA level. By treating with protein synthesis inhibitor cycloheximide (CHX), it was revealed that MTO1 did not affect the protein stability of Eg5. RNA-pull down experiments followed by mass spectrometry revealed that MTO1 interacted with tumor necrosis factor receptor associated factor 4 (TRAF4), and sequester TRAF4 from activating Eg5 translation, thereby inhibiting the Eg5 protein level. Taken together, the data reveal a regulatory mechanism by circRNAMTO1 to control cell viability and monastrol resistance in breast cancer cells.
Assuntos
Antimitóticos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , RNA/metabolismo , Fator 4 Associado a Receptor de TNF/genética , Antimitóticos/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cicloeximida/farmacologia , Regulação para Baixo , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Cinesinas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , RNA/genética , RNA Circular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA , Transdução de Sinais/genética , Fator 4 Associado a Receptor de TNF/metabolismo , Tionas/farmacologia , Tionas/uso terapêutico , Regulação para CimaRESUMO
This post hoc subgroup analysis of a large phase 3 study compared the efficacy and safety of eribulin versus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who received second-line treatment. In the phase 3 study, women with advanced/metastatic breast cancer and ≤ 3 prior chemotherapies were randomized 1:1 to eribulin mesilate 1.4 mg/m2 intravenously on days 1 and 8, or twice-daily oral capecitabine 1.25 g/m2 on days 1-14 (21-day cycles). This analysis included 392 patients. Median overall survival was longer in patients receiving eribulin compared with capecitabine (16.1 vs 13.5 months, respectively; HR 0.77, P = 0.026). Median progression-free survival and response rates were similar between arms. Both treatments had manageable safety profiles.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Antimitóticos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Capecitabina/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Resultado do TratamentoRESUMO
Paclitaxel is a successful anti-cancer drug that kills cancer cells in two-dimensional culture through perturbation of mitosis, but whether it causes tumour regression by anti-mitotic actions is controversial. Drug candidates that specifically target mitosis, including inhibitors of kinesin-5, AurkA, AurkB and Plk1, disappointed in the clinic. Current explanations for this discrepancy include pharmacokinetic differences and hypothetical interphase actions of paclitaxel. Here, we discuss post-mitotic micronucleation as a special activity of taxanes that might explain their higher activity in solid tumours. We review data showing that cells which exit mitosis in paclitaxel are highly micronucleated and suffer post-mitotic DNA damage, and that these effects are much stronger for paclitaxel than kinesin-5 inhibitors. We propose that post-mitotic micronucleation promotes inflammatory signalling via cGAS-STING and other pathways. In tumours, this signalling may recruit cytotoxic leucocytes, damage blood vessels and prime T-cell responses, leading to whole-tumour regression. We discuss experiments that are needed to test the micronucleation hypothesis, and its implications for novel anti-mitotic targets and enhancement of taxane-based therapies.
Assuntos
Anti-Inflamatórios/farmacologia , Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Antimitóticos/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêuticoRESUMO
INTRODUCTION: Mitosis is necessary to sustain life and is followed immediately by cell division into two daughter cells. Microtubules play a key role in the formation of the mitotic spindle apparatus and cytokinesis at the end of mitosis. Various anti-microtubule agents such as taxanes and vinca alkaloids are widely used in the treatment of advanced non-small cell lung cancer (NSCLC) but their use is associated with hematologic toxicity profile, acquired resistance and hypersensitivity reactions. Areas covered: The Nab-paclitaxels are the more recent antimitotic agents approved in NSCLC showing a better tolerability and activity when compared to previous ones. Despite this, the outcome of patients with advanced non-small cell lung cancer is poor. Due to the key role of mitosis, research is focused on the identification of new mitotic drug targets other than microtubule inhibitors, such as cell cycle targets, aurora kinases and Polo-like kinases. Expert opinion: Despite improvements in chemotherapeutic choices and supportive care, the majority of patients experience a deteriorating quality of life and significant toxicities associated to a poor outcome. Thus, the therapeutic management of patients with advanced NSCLC represents an ongoing challenge and novel agents targeting mitosis are under investigation.
Assuntos
Antimitóticos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antimitóticos/efeitos adversos , Antimitóticos/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/patologia , Mitose , Terapia de Alvo Molecular , Qualidade de VidaRESUMO
Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells 'slip' to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.