RESUMO
Cancer prevails as one of the major health concerns worldwide due to the consistent rise in incidence and lack of effective therapies. Previous studies identified the peptides KLKKNL, MLKSKR, and KKYRVF from Salvia hispanica seeds and stated their selective anticancer activity. Thus, this study aimed to determine the cell death pathway induced by these peptides on five cancer cell lines (MCF-7, Caco2, HepG2, DU145, and HeLa). Based on the results of this work, it is possible to suggest that KLKKNL primarily induces selective cancer cell death through the apoptotic pathway in the Caco2 and HeLa lines. On the other hand, the peptide KKYRVF reported the highest statistical (p < 0.05) selective cytotoxic effect on the MCF-7, Caco2, HepG2, and DU145 cancer cell lines by induction of the necrotic pathway. These findings offer some understanding of the selective anticancer effect of KLKKNL, MLKSKR, and KKYRVF.
Assuntos
Apoptose , Peptídeos , Salvia , Sementes , Humanos , Sementes/química , Peptídeos/farmacologia , Peptídeos/química , Apoptose/efeitos dos fármacos , Salvia/química , Linhagem Celular Tumoral , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proliferação de Células/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Plantas/farmacologia , Proteínas de Plantas/químicaRESUMO
Among the most malignant cancers, oral squamous cell carcinoma (OSCC) stands out as the most common malignant head and neck tumor. Despite advances in the field of treatment, the prognosis of patients with OSCC remains poor. Aiming to overcome the limitations of the currently existing therapies against OSCC, the present work aims to investigate the potential of photodynamic therapy (PDT) with phenothiazine derivatives used alone or in combination. The incorporation of methylene blue (MB) and toluidine blue (TB) was evaluated in OSCC cell lines (HSC-3 and SCC-9) and a nontumor cell line (Hfib). Both compounds exhibited concentration and time-dependent incorporation, with higher rates observed in tumor cells. Regarding dark-phase cytotoxic activity, SCC-9 cells were the most sensitive cell line with an IC50 value of 362.6 µM and 41.4 µM for MB and TB, respectively. Using PDT, all lineages showed greater sensitivity, presenting lower IC50 values when compared to the dark phase values. The combination index values of 0.69 (dark phase) and 0.73 (clear phase) associated with concave isobolograms, in both phases, revealed that MB and TB have synergistic effects when combined against SCC-9 cells. These findings suggest that MB or TB assisted with PDT holds promise for OSCC treatment.
RESUMO
BACKGROUND: In the last decade, cancer has been a leading cause of death worldwide. Despite the impressive progress in cancer therapy, firsthand treatments are not selective to cancer cells and cause serious toxicity. Thus, the design and development of selective and innovative small molecule drugs is of great interest, particularly through in silico tools. OBJECTIVE: The aim of this review is to analyze different subsections of computer-aided drug design (CADD) in the process of discovering anticancer drugs. METHODS: Articles from the 2008-2021 timeframe were analyzed and based on the relevance of the information and the JCR of its journal of precedence, were selected to be included in this review. RESULTS: The information collected in this study highlights the main traditional and novel CADD approaches used in anticancer drug discovery, its sub-segments, and some applied examples. Throughout this review, the potential use of CADD in drug research and discovery, particularly in the field of oncology, is evident due to the many advantages it presents. CONCLUSION: CADD approaches play a significant role in the drug development process since they allow a better administration of resources with successful results and a promising future market and clinical wise.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Desenho Assistido por Computador , Desenho de Fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Neoplasias/tratamento farmacológicoRESUMO
The development of cancers is often linked to the alteration of essential redox processes, and therefore, oxidoreductases involved in such mechanisms can be considered as attractive molecular targets for the development of new therapeutic strategies. On the other hand, for more than two decades, transition metals derivatives have been leading the research on drugs as alternatives to platinum-based treatments. The success of such compounds is particularly due to their attractive redox kinetics properties, favorable oxidation states, as well as routes of action different to interactions with DNA, in which redox interactions are crucial. For instance, the activity of oxidoreductases such as PHD2 (prolyl hydroxylase domain-containing protein) which can regulate angiogenesis in tumors, LDH (lactate dehydrogenase) related to glycolysis, and enzymes, such as catalases, SOD (superoxide dismutase), TRX (thioredoxin) or GSH (glutathione) involved in controlling oxidative stress, can be altered by metal effectors. In this review, we wish to discuss recent results on how transition metal complexes have been rationally designed to impact on redox processes, in search for effective and more specific cancer treatments.
RESUMO
Intestinal mucositis is a clinically relevant side effect of anticancer therapies. It is experienced by 60-100% of patients undergoing treatment with high doses of chemotherapy, radiation therapy, and bone marrow transplantation. Intestinal mucositis can manifest as pain, weight loss, inflammation, diarrhea, rectal bleeding, and infection; affecting normal nutritional intake and intestinal function. It often impacts adherence to anticancer therapy as it frequently limits patient's ability to tolerate treatment, causing schedule delays, interruptions, or premature discontinuation. In some cases, local and systemic secondary infections are observed, increasing the costs toward medical care and hospitalization. Several strategies for managing mucositis are available which do not always halt this condition. In this context, new therapeutic strategies are under investigation to prevent or treat intestinal mucositis. Polysaccharides from natural resources have recently become promising molecules against intestinal damage due to their ability to promote mucosal healing and their anti-inflammatory actions. These effects are associated with the protection of intestinal mucosa and regulation of microbiota and immune system. This review aims to discuss the recent advances of polysaccharides from natural resources as potential therapies for intestinal mucositis. The source, species, doses, treatment schedules, and mechanisms of action of polysaccharides will be discussed in detail.
RESUMO
p53 is a critical tumor suppressor that functions as a transcription factor. Mutations in the TP53 gene are observed in more than 50% of cancer cases worldwide. Several of these mutations lead to a less stable, aggregation-prone protein that accumulates in cancer cells. These mutations are associated with a gain of oncogenic function, which leads to cancer progression. p53 amyloid aggregation is a common feature in most of these mutants; thus, it can be used as a druggable target to reactivate or induce the degradation of p53 and promote a retraction in the aggressive pattern of mutant p53-containing cells. We show here a series of experiments for the screening and validation of new p53 antiamyloid compounds.
Assuntos
Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Mutantes , Dobramento de Proteína , Proteína Supressora de Tumor p53/química , Antineoplásicos/farmacologia , Proliferação de Células , Citometria de Fluxo , Humanos , Cinética , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica , Dobramento de Proteína/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
In this study, we report the synthesis and structural characterization of a series of thiosemicarbazone and 4-thiazolidinones derivatives, as well as their in vitro antiproliferative activity against eight human tumor cell lines. For the most potent compound further studies were performed evaluating cell death induction, cell cycle profile, ctDNA interaction and topoisomerase IIα inhibition. A synthetic three-step route was established for compounds (2a-e and 3a-d) with yields ranging from 32 to 95%. Regarding antiproliferative activity, compounds 2a-e and 3a-d showed mean GI50 values ranging between 1.1 µM (2b) - 84.65 µM (3d). Compound 2b was the most promising especially against colorectal adenocarcinoma (HT-29) and leukemia (K562) cells (GI50 = 0.01 µM for both cell lines). Mechanism studies demonstrated that 24 h-treatment with compound 2b (5 µM) induced phosphatidylserine residues exposition and G2/M arrest on HT-29 cells. Moreover, 2b (50 µM) was able to interact with ctDNA and inhibited topoisomerase IIα activity. These results demonstrate the importance of thiosemicarbazone, especially the derivative 2b, as a promising candidate for anticancer therapy.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Indóis/farmacologia , Tiazolidinas/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
Microtubules are highly dynamic assemblies of α/ß-tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (ßI) and class III (ßIII) ß-tubulin isotypes in breast and lung cancers and the highly expressed class VI (ßVI) ß-tubulin isotype in normal blood cells have increased the interest for designing specific tubulin-binding anticancer therapies. To this end, we employed our previously proposed model of the ß-tubulin-nocodazole complex, supported by the recently determined X-ray structure, to identify the fundamental structural differences between ß-tubulin isotypes. Moreover, we employed docking and molecular dynamics (MD) simulations to determine the binding mode of a series of benzimidazole-2-carbamete (BzC) derivatives in the ßI-, ßIII-, and ßVI-tubulin isotypes. Our results demonstrate that Ala198 in the ßVI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between ßI- and ßIII-BzC complexes were observed; however, Ser239 in the ßIII isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the ß-tubulin-BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics.
Assuntos
Benzimidazóis/química , Carbamatos/química , Moduladores de Tubulina/química , Sequência de Aminoácidos , Animais , Sítios de Ligação , Carbamatos/metabolismo , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Alinhamento de Sequência , Termodinâmica , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismoRESUMO
As the use of oral chemotherapy continues to rise, new approaches are needed to ensure patient safety. To help address this issue, the American Society of Clinical Oncology/Oncology Nursing Society (ONS) Chemotherapy Administration Safety Standards were expanded in 2013 to include additional measures addressing oral anticancer drugs (OACs). Because minimal data assessing the application of these standards exist, ONS conducted an independent survey of oncology nurses to evaluate the application of these standards in practice as they relate to several areas of OAC use: assessment, consent, patient education, drug verification, and monitoring. The data revealed that, although the standards are followed in many settings, a large number of settings do not have processes in place to support safety standards and ensure patient safety when administering OACs. Information gained in this informal survey can be used to guide additional research and educational initiatives.