RESUMO
Due to their manifold biological activities, natural products such as triterpenoids have advanced to represent excellent leading structures for the development of new drugs. For this reason, we focused on the syntheses and cytotoxic evaluation of derivatives obtained from gypsogenin, hederagenin, and madecassic acid, cytotoxicity increased-by and large-from the parent compounds to their acetates. Another increase in cytotoxicity was observed for the acetylated amides (phenyl, benzyl, piperazinyl, and homopiperazinyl), but a superior cytotoxicity was observed for the corresponding rhodamine B conjugates derived from the (homo)-piperazinyl amides. In particular, a madecassic acid homopiperazinyl rhodamine B conjugate 24 held excellent cytotoxicity and selectivity for several human tumor cell lines. Thus, this compound was more than 10,000 times more cytotoxic than parent madecassic acid for A2780 ovarian cancer cells. We assume that the presence of an additional hydroxyl group at position C-6 in derivatives of madecassic, as well as the (2α, 3ß) configuration of the acetates in ring A, had a beneficial effect onto the cytotoxicity of the conjugates, as well as onto tumor/non-tumor cell selectivity.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Triterpenos , Amidas/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Feminino , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/farmacologiaRESUMO
Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.
Assuntos
Camptotecina/análogos & derivados , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neuroblastoma/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Tocoferóis/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neuroblastoma/patologia , Fatores de Risco , Análise de Sobrevida , Tocoferóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The epidermal growth factor receptor (EGFR) is a key target in anticancer research, whose aberrant function in malignancies has been linked to severe irregularities in critical cellular processes, including cell cycle progression, proliferation, differentiation, and survival. EGFR mutant variants, either transmembrane or translocated to the mitochondria and/or the nucleus, often exhibit resistance to EGFR inhibitors. The ability to noninvasively image and quantify EGFR provides novel approaches in the detection, monitoring, and treatment of EGFR-related malignancies. The current study aimed to deliver a new theranostic agent that combines fluorescence imaging properties with EGFR inhibition. This was achieved via conjugation of an in-house-developed ((4-bromophenyl)amino)quinazoline inhibitor of mutant EGFR-TK, selected from a focused aminoquinazoline library, with a [Ru(bipyridine)3]2+ fluorophore. A triethyleneglycol-derived diamino linker featuring (+)-ionizable sites was employed to link the two functional moieties, affording two unprecedented Ru conjugates with 1:1 and 2:1 stoichiometry of aminoquinazoline to the Ru complex (mono-quinazoline-Ru-conjugate and bis-quinazoline-Ru-conjugate, respectively). The bis-quinazoline-Ru-conjugate, which retains an essential inhibitory activity, was found by fluorescence imaging to be effectively uptaken by Uppsala 87 malignant glioma (grade IV malignant glioma) cells. The fluorescence imaging study and a time-resolved fluorescence resonance energy transfer study indicated a specific subcellular distribution of the conjugate that coincides with that of a mitochondria-targeted dye, suggesting mitochondrial localization of the conjugate and potential association with mitochondria-translocated forms of EGFR. Mitochondrial localization was further documented by the specific concentration of the bis-quinazoline-Ru-conjugate in a mitochondrial isolation assay.
Assuntos
Neoplasias do Colo/patologia , Glioblastoma/patologia , Mitocôndrias/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Rutênio/química , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Extensão Extranodal , Corantes Fluorescentes , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Inibidores de Proteínas Quinases/química , Frações SubcelularesRESUMO
Xanthohumol (XN) is a hop-derived prenylflavonoid and have been reported to exhibit anticancer properties in several types of cancer. It presents a great interest against colon cancer due to high exposure of this compound in this tissue. Metastatic SW620 cell line was treated with doses ranging from 0.001 to 10 µM of XN to assess their effects on cell viability and mitochondrial function. At low concentrations, XN had no effect on assays carried out, but high concentration of XN led to a decrease in cell viability. In addition, at 10 µM XN, it gave rise to an increase in ROS production accompanied by a decrease in OXPHOS complexes and sirtuin 1 protein expression levels. These results suggest that XN could act as a mitocan and impairs mitochondrial function.
Assuntos
Flavonoides/farmacologia , Mitocôndrias/efeitos dos fármacos , Propiofenonas/farmacologia , Cerveja , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo , Humanos , Humulus , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismoRESUMO
Identification of novel drug targets and chemotherapeutic agents is a high priority in the fight against cancer. Here, we report that MAD-28, a designed cluvenone (CLV) derivative, binds to and destabilizes two members of a unique class of mitochondrial and endoplasmic reticulum (ER) 2Fe-2S proteins, mitoNEET (mNT) and nutrient-deprivation autophagy factor-1 (NAF-1), recently implicated in cancer cell proliferation. Docking analysis of MAD-28 to mNT/NAF-1 revealed that in contrast to CLV, which formed a hydrogen bond network that stabilized the 2Fe-2S clusters of these proteins, MAD-28 broke the coordinative bond between the His ligand and the cluster's Fe of mNT/NAF-1. Analysis of MAD-28 performed with control (Michigan Cancer Foundation; MCF-10A) and malignant (M.D. Anderson-metastatic breast; MDA-MB-231 or MCF-7) human epithelial breast cells revealed that MAD-28 had a high specificity in the selective killing of cancer cells, without any apparent effects on normal breast cells. MAD-28 was found to target the mitochondria of cancer cells and displayed a surprising similarity in its effects to the effects of mNT/NAF-1 shRNA suppression in cancer cells, causing a decrease in respiration and mitochondrial membrane potential, as well as an increase in mitochondrial iron content and glycolysis. As expected, if the NEET proteins are targets of MAD-28, cancer cells with suppressed levels of NAF-1 or mNT were less susceptible to the drug. Taken together, our results suggest that NEET proteins are a novel class of drug targets in the chemotherapeutic treatment of breast cancer, and that MAD-28 can now be used as a template for rational drug design for NEET Fe-S cluster-destabilizing anticancer drugs.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proteínas Mitocondriais/química , Ribonucleoproteínas/química , Neoplasias da Mama/química , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Análise por Conglomerados , Desenho de Fármacos , Feminino , Humanos , Proteínas Ferro-Enxofre/química , Células MCF-7 , Conformação Molecular , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Software , Xantonas/químicaRESUMO
Tumor metabolism is a crucial aspect of cancer development, and mitochondria plays a significant role in the aggressiveness and metastasis of tumors. As a result, mitochondria have become a promising therapeutic target in cancer treatment, leading to the development of compounds known as mitocans. In our group, we have consolidated the search of anticancer therapies based on natural products derived from plants, obtaining extracts such as P2Et from Caesalpinia spinosa and Anamu-SC from Petiveria alliacea, which have been shown to have antitumor activities in different cancer models. These extracts, due to their complex molecular composition, can interfere with multiple functions during tumor progression. To better understand how these natural products operate (P2Et and Anamu-SC), we constructed a model using 4T1 murine breast cancer cells with reduced expression of genes associated with glycolysis (Hexokinase-2) and mitochondrial function (Cqbp). The results indicate that the cells were more sensitive to the Anamu-SC extract, showing significant decreases in glucose consumption, ATP production, and oxygen consumption rate. Additionally, we observed changes in mitochondrial function, which reduced the cells' ability to migrate, particularly when C1qbp was silenced. This triple-negative breast cancer model allows us to identify potential natural products that can modulate tumor cell metabolism.
Assuntos
Movimento Celular , Mitocôndrias , Extratos Vegetais , Neoplasias de Mama Triplo Negativas , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Animais , Movimento Celular/efeitos dos fármacos , Camundongos , Feminino , Linhagem Celular Tumoral , Humanos , Glicólise/efeitos dos fármacos , Fabaceae/químicaRESUMO
Parent pentacyclic triterpenoic acids such as ursolic-, oleanolic, glycyrrhetinic, betulinic and boswellic acid were converted into their acetylated piperazinyl amides that were coupled with rhodamine B. SRB assays to evaluate their cytotoxicity showed all of these triterpene-homopiperazinyl-rhodamine adducts 16-20 being highly cytotoxic for a panel of human tumor cell lines even in nanomolar concentrations while being significantly less cytotoxic for non-malignant cells. Interestingly enough, these compounds were even more cytotoxic than previously prepared piperazinyl analogs, thus making the homopiperazinyl spacer a very interesting scaffold for the development of biologically active compounds. Extra staining experiments showed that the cytostatic effect of compounds 18 and 20 onto A2780 cancer cells is due to their ability to act as a mitocan.
Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Rodaminas/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Microscopia de Fluorescência , Estrutura Molecular , Células NIH 3T3 , Piperazina , Piperazinas/química , Rodaminas/química , Relação Estrutura-Atividade , Triterpenos/síntese química , Triterpenos/químicaRESUMO
Triterpenoic acids, ursolic acid (1), oleanolic acid (2), glycyrrhetinic acid (3) and betulinic acid (4) were converted into their corresponding methyl 5-8 and benzyl esters 9-12 or benzyl amides 21-24. These derivatives served as starting materials for the synthesis of pink colored rhodamine B derivatives 25-36 which were screened for cytotoxicity in colorimetric SRB assays. All of the compounds were cytotoxic for a variety of human tumor cell lines. The activity of the benzyl ester derivatives 29-32 was lower than the cytotoxicity of the methyl esters 25-28. The benzyl amides 33-36 were the most cytotoxic compounds of this series. The most potential compound was a glycyrrhetinic acid rhodamine B benzyl amide 35. This compound showed activity against the different cancer cell lines in a two-digit to low three-digit nano-molar range. Staining experiments combined with fluorescence microscopy showed that this compound triggered apoptosis in A2780 ovarian carcinoma cells and acted as a mitocan.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ésteres/farmacologia , Mitocôndrias/efeitos dos fármacos , Rodaminas/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres/síntese química , Ésteres/química , Humanos , Microscopia de Fluorescência , Estrutura Molecular , Rodaminas/síntese química , Rodaminas/química , Relação Estrutura-Atividade , Triterpenos/químicaRESUMO
Based on their biological activity natural products continue to represent optimal lead structures for the development of novel drug candidates. We focused on the syntheses of several derivatives of the triterpene asiatic acid and on the evaluation of their cytotoxic activity in a photometric sulforhodamin B assay. Especially, benzamide 2 and rhodamine B conjugate 11 show a distinct cytotoxicity for several human tumor cell lines, e.g. EC50 (A2780)â¯=â¯110⯱â¯1â¯nM and EC50 (A2780)â¯=â¯8⯱â¯2â¯nM, respectively. Interestingly, compound 11 showed for two human tumor cell lines (HT29 and 518A2) non-linear, bimodal dose-response relationships.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Animais , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Células NIH 3T3 , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-AtividadeRESUMO
The hydrophobicity of vitamin E poses transport and metabolic challenges to regulate its bioavailability and to prevent its accumulation in lipid-rich tissues such as adipose tissue, brain, and liver. Water-soluble precursors of vitamin E (α-tocopherol, αT), such as its esters with acetate (αTA), succinate (αTS), or phosphate (αTP), have increased solubility in water and stability against reaction with free radicals, but they are rapidly converted during their uptake into the lipid-soluble vitamin E. Therefore, the bioavailability of these precursors as intact molecules is low; nevertheless, at least for αTS and αTP, the recent research has revealed unique regulatory effects on signal transduction and gene expression and the modulation of cellular events ranging from proliferation, survival/apoptosis, lipid uptake and metabolism, phagocytosis, long term potentiation, cell migration, telomere maintenance, and angiogenesis. Moreover, water-soluble derivatives of vitamin E including some based on αTP are increasingly used as components of nanocarriers for enhanced and targeted delivery of drugs and other molecules (vitamins, including αT and αTP itself, vitamin D3, carnosine, caffeine, docosahexaenoic acid (DHA), insulin) and cofactors such as coenzyme Q10. In this review, the chemical characteristics, transport, metabolic pathways, and molecular mechanisms of action of αTP in cells and tissues are summarized and put into perspective with its possible role in the prevention of a number of diseases.
Assuntos
Deficiência de Vitamina E/tratamento farmacológico , Vitaminas/química , Vitaminas/farmacologia , alfa-Tocoferol/análogos & derivados , Humanos , Solubilidade , alfa-Tocoferol/química , alfa-Tocoferol/farmacologiaRESUMO
Oleanolic acid derivatives exhibit potent anticancer activities against numerous types of cancer. However, the antitumor activity of oleanolic acid methylester (OAME), an oleanolic acid derivative, against prostate cancer has not been studied. Hence, the present work was conducted to study the anticancer activities of OAME. Viability assay showed that treatment of cancer cells with OAME induced a significant cell death in concentration- and time-dependent manner. Of note, OAME displayed a selective cytotoxicity against cancer cells compared to normal epithelial cells. Cells treated with OAME exhibited cell cycle arrest at both G1 and G2. Apoptotic induction potential of OAME was demonstrated using Annexin V assay, caspase activation, and DNA fragmentation methods Mechanistically, the results revealed that OAME strongly impacted the intrinsic apoptotic pathway in a concentration-dependent manner, as demonstrated by loss of mitochondrial membrane potential and release cytochrome c into the cytosol. ROS scavenger completely abrogated OAME-induced cell death. In vivo, OAME exerted concentration- dependent antiproliferative effect, associated with a significant level of apoptosis, potent antiangiogenic activity, and downregulation of survivin. This study provides significant insight into the therapeutic activities of OAME against prostate cancer in vitro and in vivo, suggesting that OAME might serve as a promising lead compound to treat hormonal-resistant prostate cancer.
Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , Citotoxinas/farmacologia , Ácido Oleanólico/farmacologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Embrião de Galinha , Citotoxinas/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Ácido Oleanólico/análogos & derivados , Neoplasias de Próstata Resistentes à Castração/patologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Triterpenoic acids 1-6 exhibited very low or no cytotoxicity at all, but their corresponding 2,3-di-O-acetyl-piperazinyl amides 13-18 showed low EC50 values for several human tumor cell lines. Their cytotoxicity, however, was also high for the non-malignant mouse fibroblasts NIH 3T3. A significant improvement was achieved by preparing the rhodamine B derivatives 19-24. While rhodamine B is not cytotoxic (up to a concentration of 30µM - cut-off of the assay), the triterpenoid piperazine-spacered rhodamine B derivatives were cytotoxic in nano-molar concentration. Compound 24 (a diacetylated maslinic acid derivative) was most toxic for several human tumor cell lines but less toxic for mouse fibroblasts NIH 3T3. Staining and double-staining experiments revealed 24 to act as a mitocan.
Assuntos
Mitocôndrias/efeitos dos fármacos , Rodaminas/química , Triterpenos/farmacologia , Triterpenos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Células NIH 3T3 , Relação Estrutura-Atividade , Triterpenos/químicaRESUMO
Acute myeloid leukemia (AML) is a clonal hematologic neoplasm characterized by heterogeneity of genetic abnormalities found at diagnosis. These abnormalities serve to classify patients by risk group into low, intermediate, and high risk. It also provides specific targets for the development of new combinational therapies. However, because of the heterogeneity of genetic abnormalities, targeted therapy is not always possible. Altered mitochondrial metabolism is a common feature in cancer cells, a phenomenon first described by Otto Warburg. In AML patients, the discovery of mutations in the isocitrate dehydrogenase gene provided for the first time a link between altered mitochondrial metabolism and AML. This raised the possibility of testing drugs known as mitocans for new combinational therapeutic approaches. Mitocans are a diverse group of anti-cancer compounds that target mitochondria. They disrupt energy production leading to enhanced generation of reactive oxygen species along with the activation of the intrinsic pathway of apoptosis. The present review discusses the different types of mitocans and their mechanism of action along with preclinical and clinical studies in AML (AU)