RESUMEN
Cancer is the second leading cause of death in the world following cardiovascular disease. Its treatment, including radiation therapy and surgical removal of the tumour, is based on pharmacotherapy, which prompts a constant search for new and more effective drugs. There are high costs associated with designing, synthesising, and marketing new substances. Drug repositioning is an attractive solution. Fluoroquinolones make up a group of synthetic antibiotics with a broad spectrum of activity in bacterial diseases. Moreover, those compounds are of particular interest to researchers as a result of reports of their antiproliferative effects on the cells of the most lethal cancers. This article presents the current progress in the development of new fluoroquinolone derivatives with potential anticancer and cytotoxic activity, as well as structure-activity relationships, along with possible directions for further development.
Asunto(s)
Antineoplásicos , Fluoroquinolonas , Fluoroquinolonas/química , Fluoroquinolonas/farmacología , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Neoplasias/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Antibacterianos/química , Reposicionamiento de Medicamentos , Proliferación Celular/efectos de los fármacosRESUMEN
Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨm), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.
Asunto(s)
Antineoplásicos , Apoptosis , Autofagia , Proliferación Celular , Neoplasias de la Mama Triple Negativas , Humanos , Apoptosis/efectos de los fármacos , Femenino , Proliferación Celular/efectos de los fármacos , Autofagia/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/uso terapéutico , Compuestos de Organoselenio/química , Supervivencia Celular/efectos de los fármacos , Ésteres/química , Ésteres/farmacología , Células MCF-7RESUMEN
In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.
Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Sulfonamidas , Triazinas , Humanos , Triazinas/farmacología , Triazinas/química , Triazinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonamidas/química , Sulfonamidas/síntesis química , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Tumorales Cultivadas , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Femenino , Línea Celular Tumoral , Esferoides Celulares/efectos de los fármacosRESUMEN
The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K2PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2CO3. In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy.
Asunto(s)
Antineoplásicos , Apoptosis , Neoplasias de la Mama , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Tiosemicarbazonas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Tiosemicarbazonas/farmacología , Tiosemicarbazonas/química , Tiosemicarbazonas/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Apoptosis/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Femenino , Relación Dosis-Respuesta a Droga , Línea Celular Tumoral , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/química , Compuestos Organoplatinos/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Platino (Metal)/química , Platino (Metal)/farmacología , Autofagia/efectos de los fármacosRESUMEN
Vaccinium uliginosum L. (commonly known as bog bilberry) and Vaccinium myrtillus L. (commonly known as bilberry) are species of the genus Vaccinium (family Ericaceae). The red-purple-blue coloration of blueberries is attributed largely to the anthocyanins found in bilberries. Anthocyanins, known for their potent biological activity as antioxidants, have a significant involvement in the prophylaxis of cancer or other diseases, including those of metabolic origin. Bilberry is the most important economically wild berry in Northern Europe, and it is also extensively used in juice and food production. A review of the latest literature was performed to assess the composition and biological activity of V. uliginosum and V. myrtillus. Clinical studies confirm the benefits of V. uliginosum and V. myrtillus supplementation as part of a healthy diet. Because of their antioxidant, anti-inflammatory, anti-cancer, and apoptosis-reducing activity, both bog bilberries and bilberries can be used interchangeably as a dietary supplement with anti-free radical actions in the prevention of cancer diseases and cataracts, or as a component of sunscreen preparations.
Asunto(s)
Arándanos Azules (Planta) , Vaccinium myrtillus , Antocianinas/farmacología , Alimentos Funcionales , Frutas , Antioxidantes/farmacología , Extractos Vegetales/farmacologíaRESUMEN
In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as dual inhibitors targeting topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231). The investigated compounds (1-3) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8- and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1-3 and their effects on specific cytochrome P450 enzymes were evaluated.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Femenino , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Apoptosis , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Semicarbacidas/farmacologíaRESUMEN
Disturbing cancer statistics, especially for breast cancer, are becoming a rationale for the development of new anticancer therapies. For the past several years, studies have been proving a greater role of selenium in the chemoprevention of many cancers than previously considered; hence, a trend to develop compounds containing this element as potential agents with anticancer activity has been set for some time. Therefore, our study aimed to evaluate the anticancer activity of novel selenoesters (EDA-71, E-NS-4) in MCF-7 and MDA-MB-231 human breast cancer cells. The assays evaluating proliferation and cell viability, and flow cytometer analysis of apoptosis/autophagy induction, changes in mitochondrial membrane potential, disruption of cell cycle phases, and protein activity of mTOR, NF-κB, cyclin E1/A2, and caspases 3/7, 8, 9, 10 were performed. The obtained results indicate that the tested selenoesters are highly cytotoxic and exhibit antiproliferative activity at low micromolar doses (<5 µM) compared with cisplatin. The most active compoundEDA-71highly induces apoptosis, which proceeds via both pathways, as evidenced by the activation of all tested caspases. Furthermore, we observed the occurrence of autophagy (↓ mTOR levels) and cell cycle arrest in the S or G2/M phase (↓ cyclin E1, ↑ cyclin A2).
RESUMEN
There is a need for new, safer, and more effective agents to treat cancer. Cytostatics that have transition metals at their core have attracted renewed interest from scientists. Researchers are attempting to use chemotherapeutics, such as cisplatin, in combination therapy (i.e., in order to enhance their effectiveness). Moreover, studies are being carried out to modify molecules, by developing them into multinuclear structures, linking different compounds to commonly used drugs, or encapsulating them in nanoparticles to improve pharmacokinetic parameters, and increase the selectivity of these drugs. Therefore, we attempted to organize recent drug findings that contain palladium and platinum atoms in their structures.
Asunto(s)
Antineoplásicos/química , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/química , Paladio/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Sinergismo Farmacológico , Humanos , Compuestos Organoplatinos/farmacología , Compuestos Organoplatinos/uso terapéuticoRESUMEN
This review answers the question of why selenium is such an important trace element in the human diet. Daily dietary intake of selenium and its content in various food products is discussed in this paper, as well as the effects of its deficiency and excess in the body. Moreover, the biological activity of selenium, which it performs mainly through selenoproteins, is discussed. These specific proteins are responsible for thyroid hormone management, fertility, the aging process, and immunity, but their key role is to maintain a redox balance in cells. Furthermore, taking into account world news and the current SARS-CoV-2 virus pandemic, the impact of selenium on the course of COVID-19 is also discussed. Another worldwide problem is the number of new cancer cases and cancer-related mortality. Thus, the last part of the article discusses the impact of selenium on cancer risk based on clinical trials (including NPC and SELECT), systematic reviews, and meta-analyses. Additionally, this review discusses the possible mechanisms of selenium action that prevent cancer development.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19/metabolismo , Dieta , Neoplasias , SARS-CoV-2/metabolismo , Selenio/uso terapéutico , Oligoelementos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
The high number of new cancer incidences and the associated mortality continue to be alarming, leading to the search for new therapies that would be more effective and less burdensome for patients. As there is evidence that Se compounds can have chemopreventive activity, studies have begun to establish whether these compounds can also affect already existing cancers. This review aims to discuss the different classes of Se-containing compounds, both organic and inorganic, natural and synthetic, and the mechanisms and molecular targets of their anticancer activity. The chemical classes discussed in this paper include inorganic (selenite, selenate) and organic compounds, such as diselenides, selenides, selenoesters, methylseleninic acid, 1,2-benzisoselenazole-3[2H]-one and selenophene-based derivatives, as well as selenoamino acids and Selol.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Compuestos de Selenio/uso terapéutico , Animales , Antineoplásicos/química , Quimioprevención/métodos , Ensayos Clínicos como Asunto , Humanos , Neoplasias/metabolismo , Neoplasias/prevención & control , Compuestos de Selenio/químicaRESUMEN
Novel transition metal complexes (Au, Pd, Pt) with berenil and 2-(1-methyl-5-nitroimidazol-2-yl)ethanol were obtained through two-step synthesis. The cytotoxicity assay against MCF-7 and MDA-MB-231 breast cancer cells revealed that novel platinum and palladium complexes cause a reduction on the viability of MCF-7 and MDA-MB-231 breast cancer cells to a greater extent than cisplatin. The complexes showed lower cytotoxicity on normal MCF-10A human breast epithelial cells than on tumor cells. Furthermore, we observed that these complexes selectively concentrate in tumor cell mitochondria due to the characteristic for these cells increased membrane potential that may explain their increased proapoptotic activity. The activity of the synthesized compounds against topoisomerase type IIα and their increased impact on DNA defragmentation also were documented. The novel complexes also induced autophagosome changes and inhibited tumor growth in xenograft models (established using breast cancer cells).