RESUMO
Cytochrome P450 (CYP) 1B1 has been found to be overexpressed specifically in tumor tissues at an early stage, which makes it a potential cancer biomarker for molecular imaging. Multimodal imaging combines different imaging modalities and offers more comprehensive information. Thus, imaging probes bearing more than one kind of signal fragment have been extensively explored and display great promise. Herein, we developed a near infrared (NIR) probe with a chelator moiety targeting CYP1B1 by conjugating α-naphthoflavone (ANF) derivatives with both an NIR dye and a chelator for potential application in bimodal imaging. Enzymatic inhibitory studies demonstrated inhibitory activity against CYP1B1 and selectivity among CYP1 were successfully retained after chemical modification. Cell-based saturation studies indicated nanomolar range binding affinity between the probe and CYP1B1 overexpressed cancer cells. In vitro competitive binding assays monitored by confocal microscopy revealed that the probe could specifically accumulate in tumor cells. In vivo and ex vivo imaging studies demonstrated that the probe could effectively light-up the tumor tissues as early as 2â hours post-injection. In addition, the fluorescence was significantly blocked by co-injection of CYP1B1 inhibitor, which indicated the probe accumulation in tumor sites was due to specific binding to CYP1B1.
Assuntos
Quelantes , Imagem ÓpticaRESUMO
To reduce the pervasive toxicity of natural shikonin, alkannin, and their synthetic analogues and to enhance the selectivity of these chemotherapeutics toward cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized, and evaluated for its strong antitumor activity both in vitro and in vivo. It showed potent growth inhibitory effects against HCT-15, HCT-116, and K562 cells (IC50 < 1 µM), moderate antiproliferative activity toward MDA-MB-231, HepG2, PANC, Bel7402, and MGC803 cancer cells (IC50 < 10 µM), and was nontoxic to the human normal VEC and HSF cells. In vivo efficacy studies demonstrated that DMAKO-20 (10 mg/kg, i.v. on every the other day, 8 times in 14 days) resulted in 59.3% reduction in HCT-15 xenograft volume. It was as effective as the toxic antimetabolite 5-FU but revealed neither toxicity nor death in mice. The mechanistic investigations indicated that DMAKO-20 underwent the tumor-specific CYP1B1-catalyzed bioactivation to afford nitric oxide and active naphthoquinone mono-oximes, which exhibited combined anticancer effects. It was defined as a representative of the "Multi-target Anticancer Prodrugs Activated by Specific Enzymes in cancer cells". The produced active metabolites exerted anticancer effects by the direct nucleophilic alkylation and the induction of the apoptosis of cancer cells through activation of the mitochondrial pathway. The discovery of DMAKO-20 and the illustration of its molecular mechanisms may provide a new strategy to overcome the nonselective toxicity of the current chemotherapeutics.
Assuntos
Antineoplásicos/farmacologia , Citocromo P-450 CYP1B1/metabolismo , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1B1/genética , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células Hep G2 , Humanos , Células K562 , Camundongos , Naftoquinonas/química , Pró-Fármacos/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.
Assuntos
Antineoplásicos/farmacologia , Naftoquinonas/farmacologia , Oximas/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 , Humanos , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Oximas/síntese química , Oximas/química , Relação Estrutura-AtividadeRESUMO
The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.
Assuntos
Antineoplásicos/metabolismo , Microssomos Hepáticos/metabolismo , Naftoquinonas/metabolismo , Animais , Linhagem Celular Tumoral , Fluoruracila/metabolismo , Células HCT116 , Humanos , Cinética , Masculino , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A set of forty alkannin and shikonin oxime derivatives were firstly designed and synthesized. Their cytotoxicities against three kinds of tumor cells and a normal cell line were tested and compared with alkannin and shikonin. The cell-based investigation demonstrated that some oxime derivatives were more or comparatively effective to the lead compounds, especially their selective and excellent antitumor activities towards K562 cells with no toxicity in normal cells. We may conclude that oximate modification to the mother nucleus of alkannin and shikonin is an available approach to acquire potent antitumor agents.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Naftoquinonas/farmacologia , Oximas/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Células MCF-7 , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , Oximas/síntese química , Oximas/química , Relação Estrutura-AtividadeRESUMO
Cytochrome P450 1B1 (CYP1B1) is induced during the early stage of cancer and is universally overexpressed in tumors. Thus, it was considered as a potential biomarker for the monitoring of cancer. In this study, we designed and synthesized CYP1B1-targeted near-infrared (NIR) fluorescence molecular probes based on the latest reported open conformation of the CYP1B1-α-naphthoflavone (ANF) complex. According to the architecture of the open channel, we introduced linkers and a Cy5.5 fragment at the 5' position of ANF derivatives with strong CYP1B1 inhibitory activity to obtain probes 19-21. Then, in vitro cell-based studies showed that the probes could be enriched in tumor cells by binding to CYP1B1. During in vivo and ex vivo imaging in a xenograft mouse model, probe 19 with the best binding affinity was proven to be able to identify tumor sites in both fluorescence imaging and photoacoustic imaging modes.
Assuntos
Neoplasias Colorretais , Humanos , Animais , Camundongos , Citocromo P-450 CYP1B1/química , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Sondas Moleculares , Imagem MolecularRESUMO
Bombesin receptor subtype-3 (BB3, BRS-3) is an orphan Gαq protein-coupled receptor. The characterization of novel synthetic ligands for BB3 is an alternative and attractive strategy to study its diverse physiological functions. Here, we uncovered the intimate pairing of DMAKO-00 and its derivatives with BB3. Dimethyl shikonin oxime 5a (DSO-5a) was identified as the most potent agonist for BB3 (pEC50 = 8.422 in IP-1 accumulation), which was 898-fold more potent than DMAKO-00. Importantly, without brain penetration, DSO-5a improved glucose tolerance in C57BL/6 mice through BB3 and ameliorated glucose homeostasis in diabetic db/db mice. We further revealed that DSO-5a upregulated PPAR-gamma activity via BB3 through a quantitative proteomics approach. Collectively, our study demonstrated that DSO-5a, a representative compound of DMAKO-00 derivatives, is a potent, selective, and low-brain-penetrating agonist for BB3, and BB3 is a promising treatment target for type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2 , Receptores da Bombesina , Camundongos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Camundongos Endogâmicos C57BL , Glucose , BombesinaRESUMO
BACKGROUND: Androgen receptor (AR) is the main therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy (ADT) is only effective for a short period of time. Here we tested PTS33, a new sodium derivative of cryptotanshinone, which can effectively inhibit the DHT-induced AR transactivation and PCa cell growth, and then explored the effects of PTS33 on inhibiting the expressions of AR target genes and proteins. METHODS: PCa cells, LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with PTS33 and luciferase assay was used to evaluate the ability of each to regulate AR transactivation. RT-PCR was used to evaluate the mRNA levels of AR target genes such as PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR, PSA, estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and progesterone receptor (PR) protein expression. Cell growth and IC50 were determined by MTT assay after 48 hr treatment. RESULTS: Our data showed that PTS33 selectively inhibits AR activities, but PTS33 does not repress the activities of other nuclear receptors, including ERα, GR, and PR. At a low concentration, 2 µM of PTS33 effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Furthermore, our data indicated that PTS33 could modulate AR transactivation and suppress the AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration-resistant C4-2 cells. In addition, PTS33 can also inhibit estrogen/Δ5-androstenediol induced AR activities. The mechanistic studies indicate that PTS33 can inhibit AR function by suppression of AR protein expression, the AR N-C interaction, and AR-coregulator interaction. CONCLUSIONS: PTS33 has shown a good efficacy to inhibit AR transactivation, block AR regulated gene expression, and reduce cell growth in AR positive PCa cells. The structure of PTS33 could be used as a base for development of novel AR signaling inhibitors to treat PCa.
Assuntos
Adenocarcinoma/tratamento farmacológico , Fenantrenos/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular Tumoral , Receptor alfa de Estrogênio , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas de Membrana/metabolismo , Fenantrenos/síntese química , Fenantrenos/química , Antígeno Prostático Específico/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/biossíntese , Receptores de Progesterona/biossíntese , Serina Endopeptidases/metabolismoRESUMO
Shikonin, the main active ingredient of Lithospermum, and its derivatives have been proved to have antitumor effects, and the anti-tumor mechanisms involve multiple targets. Based on recent literatures, this review focuses on the antitumor effects and its mechanisms. More emphases are given on the aspects of induction of apoptosis, induction of necrosis, acting on matrix metalloproteinase, acting on the protein tyrosine kinase and antiangiogenesis. The current status and problems of shikonin derivatives in antitumor effects are simply summarized and lookout for the development of antitumor drugs with shikonin as leading compounds.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Lithospermum/química , Naftoquinonas/farmacologia , Neoplasias , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular Tumoral , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Naftoquinonas/isolamento & purificação , Naftoquinonas/uso terapêutico , Necrose , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/prevenção & controle , Plantas Medicinais/química , Proteínas Tirosina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
7-Methyl juglone as a naturally occurring naphthoquinone showed striking antibacterial, antifungal, antivirus and anticancer activity. Its derivatives had also been characterized as key intermediates in the preparation of natural naphthoquinones and anthraquinones. Herein, we reported a regioselective synthesis of 7-methyl juglone via the construction of fused polycyclic systems. The key steps of the strategy involved Stobbe condensation of 2,5-dimethoxy benzaldehyde with diethyl succinate, intramolecular cyclization, reduction, acid-facilitated debenzylation and further cerium(IV) ammonium nitrate-mediated oxidation. Compared with the reported methods employing Birch conditions in liquid ammonia or Friedel-Crafts cycloacylation with melting heat of aluminum salts, the reaction conditions in the new synthetic route were milder and suitable for large scale preparations. In addition, all of the starting materials in the synthesis were readily available. It has great implications for the design and synthesis of structurally asymmetric naphthoquinones derivatives.
Assuntos
Naftoquinonas , Antifúngicos , Ciclização , OxirreduçãoRESUMO
BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is specifically expressed in a variety of tumors which makes it a promising imaging target of tumor. OBJECTIVE: We aimed to design and synthesize CYP1B1 targeted chelators for the potential application in positron emission tomography (PET) imaging of tumor. METHODS: 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA) was connected to the CYP1B1 selective inhibitor we developed before through polyethylene glycol (PEG) linkers with different lengths. The inhibitory activities of chelators 6a-c against CYP1 family were evaluated by 7-ethoxyresorufin o-deethylation (EROD) assay. The manual docking between the chelators and the CYP1B1 was conducted subsequently. To determine the binding affinities of 6a-c to CYP1B1 in cells, we further performed a competition study at the cellular level. RESULTS: Among three chelators, 6a with the shortest linker showed the best inhibitory activity against CYP1B1. In the following molecular simulation study, protein-inhibitor complex of 6a showed the nearest F-heme distance which is consistent with the results of enzymatic assay. Finally, the cell based competitive assay proved the binding affinity of 6a-c to CYP1B1 enzyme. CONCLUSION: We designed and synthesized a series of chelators which can bind to CYP1B1 enzyme in cancer cells.To our knowledge, this work is the first attempt to construct CYP1B1 targeted chelators for radiolabeling and we hope it will prompt the application of CYP1B1 imaging in tumor detection.
Assuntos
Quelantes/farmacologia , Citocromo P-450 CYP1B1/antagonistas & inibidores , Desenho de Fármacos , Compostos Heterocíclicos/farmacologia , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Citocromo P-450 CYP1B1/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The aim of this paper is to evaluate the cellular uptake of vincristine sulfate-loaded poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles with the folic acid modification (PLGA-PEG-folate NPs). PLGA-PEG-folate NPs were prepared using a water-oil-water emulsion solvent evaporation method. The particle size, surface morphology, drug encapsulation efficiency, and the drug release behavior were investigated. The NPs exhibited a biphasic drug release with a moderate initial burst followed by a sustained release profile. Internalization of the NPs labeled with coumarin- 6 by MCF-7 (Michigan Cancer Foundation-7) human breast cancer cells was quantitatively measured by microplate reader, and qualitatively analyzed by fluorescent microscopy and confocal laser scanning microscopy. The results showed PLGA-PEG-folate NPs achieved significantly higher cellular uptake in the folic acid receptor overexpressed MCF-7 cells, compared to PLGA-mPEG NPs without the folic acid modification. Due to the enhanced cellular uptake, PLGA-PEG-folate NPs displayed the highest cytotoxicity. Judged by IC(50) after 24 h culture, the therapeutic effects of the drug formulated in the NPs with surface modification could be 1.52 times, 3.91 times higher than that of PLGA-mPEG NPs and free vincristine sulfate, respectively.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Portadores de Fármacos/química , Ácido Fólico/química , Nanopartículas/química , Polietilenoglicóis/química , Poliglactina 910/química , Vincristina/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Neoplasias da Mama/metabolismo , Sobrevivência Celular , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Microscopia de Fluorescência , Tamanho da Partícula , Células Tumorais Cultivadas , Vincristina/farmacocinéticaRESUMO
BACKGROUND: Multidrug resistance (MDR) is the resistance of cancer cells against a variety of currently used antineoplastic agents with diverse structural scaffolds and different anticancer mechanisms. It has been recognized as one of the major impediments to the successful treatment of cancer, leading to the metastasis and relapse of malignant diseases. INTRODUCTION: Collateral sensitivity (CS) is the characteristic of certain chemicals to kill the drugresistant sublines selectively over the parental cell lines from which the resistant cells were generated. The research and development of new drug candidates with collateral sensitivity will be an efficient approach to conquer multidrug resistance in cancer. We aim to provide an update on the discovery of natural products with collateral sensitivity. RESULTS AND CONCLUSION: The review focused on the characterized anticancer natural products and their derivatives with collateral sensitivity, their working mechanisms, and related structure-activity relationships, emphasizing recently identified CS compounds. According to their structural features, these MDR-targeting compounds were mainly classified into the following categories: flavonoids, terpenoids, stilbenes, alkaloids and quinones. The exploration of molecular mechanisms of collateral sensitivity and structural features of anticancer agents with collateral sensitivity provided an effective approach for the clinic treatment of MDR in cancer.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Animais , Antineoplásicos/química , Produtos Biológicos/química , Humanos , Relação Estrutura-AtividadeRESUMO
Cytochrome P450 1B1 (CYP1B1) has been well validated as an attractive target for cancer prevention and drug resistance reversal. In continuation of our interest in this area, herein, a set of forty-six 6,7,10-trimethoxy-α-naphthoflavone derivatives varying in B ring was synthesized and screened against CYP1 enzymes, leading to the identification of fluorine-containing compound 15i as the most potent and selective CYP1B1 inhibitor (IC50 value of 0.07 nM), being 84-fold more potent than that of the template molecule ANF. Alternatively, the amino-substituted derivative 13h not only possessed a potent inhibitory effect on CYP1B1 (IC50 value of 0.98 nM), but also had a substantially increased water solubility as compared with the lead ANF (311 µg/mL for 13h and <5 µg/mL for ANF). The current study expanded the structural diversity of CYP1B1 inhibitors, and compound 13h could be considered as a promising starting point with great potential for further studies.
Assuntos
Benzoflavonas/química , Benzoflavonas/farmacologia , Citocromo P-450 CYP1B1/antagonistas & inibidores , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Citocromo P-450 CYP1B1/metabolismo , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Solubilidade , Água/químicaRESUMO
BACKGROUND: Multidrug Resistance (MDR) is defined as a cross-resistance of cancer cells to various chemotherapeutics and has been demonstrated to correlate with drug efflux pumps. Visualization of drug efflux pumps is useful to pre-select patients who may be insensitive to chemotherapy, thus preventing patients from unnecessary treatment. Near-Infrared (NIR) imaging is an attractive approach to monitoring MDR due to its low tissue autofluorescence and deep tissue penetration. Molecular NIR imaging of MDR cancers requires stable probes targeting biomarkers with high specificity and affinity. OBJECTIVE: This article aims to provide a concise review of novel NIR probes and their applications in MDR cancer treatment. RESULTS: Recently, extensive research has been performed to develop novel NIR probes and several strategies display great promise. These strategies include chemical conjugation between NIR dyes and ligands targeting MDR-associated biomarkers, native NIR dyes with inherent targeting ability, activatable NIR probes as well as NIR dyes loaded nanoparticles. Moreover, NIR probes have been widely employed for photothermal and photodynamic therapy in cancer treatment, which combine with other modalities to overcome MDR. With the rapid advancing of nanotechnology, various nanoparticles are incorporated with NIR dyes to provide multifunctional platforms for controlled drug delivery and combined therapy to combat MDR. The construction of these probes for MDR cancers targeted NIR imaging and phototherapy will be discussed. Multimodal nanoscale platform which integrates MDR monitoring and combined therapy will also be encompassed. CONCLUSION: We believe these NIR probes project a promising approach for diagnosis and therapy of MDR cancers, thus holding great potential to reach clinical settings in cancer treatment.
Assuntos
Nanopartículas , Neoplasias , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Fluorescência , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fototerapia , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Cytochrome P450 1B1(CYP1B1) has been recognized as an important target for cancer prevention and drug resistance reversal. In order to obtain potent and selective CYP1B1 inhibitors, a series of forty-one α-naphthoflavone (ANF) derivatives were synthesized, characterized, and evaluated for CYP1B1, CYP1A1 and CYP1A2 inhibitory activities. A closure look into the structure-activity relationship for the inhibitory effects on CYP1B1 indicated that modification of the C ring of ANF would decrease the CYP1B1 inhibitory potency, while incorporation of substituent(s) into the different positions of the B ring yielded analogues with varying CYP1B1 inhibitory capacity. Among these derivatives, compounds 9e and 9j were identified as the most potent two selective CYP1B1 inhibitors with IC50 values of 0.49 and 0.52 nM, respectively, which were 10-fold more potent than the lead compound ANF. In addition, molecular docking and a reasonable 3D-QSAR (three-dimensional quantitative structure-activity relationship) study were performed to provide a better understanding of the key structural features influencing the CYP1B1 inhibitory activity. The results achieved in this study would lay a foundation for future development of selective, potent, low-toxic and water-soluble CYP1B1 inhibitors.
Assuntos
Benzoflavonas/farmacologia , Citocromo P-450 CYP1B1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Benzoflavonas/síntese química , Benzoflavonas/química , Citocromo P-450 CYP1B1/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Multi-drug resistance (MDR) of cancer cells is a major cause of failure in chemotherapy. To the majority of anti-cancer drugs, tumor cells are able to generate a multi-drug resistance; but there is no common views on the mechanism of MDR. This review summarizes the use of drug delivery system based on nanoparticles to overcome MDR in recent years. Three kinds including non-modified, ligand-modified and multifunctional drug delivery systems are described. Especially, the mechanism of reversing MDR based on nanoparticles is covered. Through efficiently offsetting and antagonizing the action of pumping drugs out of the tumor cells, drug delivery system based on nanoparticles can increase the concentration of the drug in tumors, while reduce the side effects on normal cells and overcome multi-drug resistance. The use of drug-loaded nanoparticles, which combines nanotechnology with the strategy of active and passive targeting administration, has shown significant prospect improving cancer therapy.
Assuntos
Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Resistência a Múltiplos Medicamentos , HumanosRESUMO
Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC)â¯>â¯1). Of these, compound 12â¯m was identified as the most effective molecule with IC50 values in the range of 0.29⯱â¯0.01 to 1.33⯱â¯0.05⯵M toward MDR sublines. Further mechanism studies demonstrated that 12â¯m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.
Assuntos
Antineoplásicos/síntese química , Resistencia a Medicamentos Antineoplásicos , Naftoquinonas/farmacologia , Oximas/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Naftoquinonas/química , Oximas/química , Relação Estrutura-Atividade , EnxofreRESUMO
A series of benzochalcone derivatives have been synthesized and evaluated for CYP1 inhibitory activity and cytotoxic properties against wild type cell lines (MCF-7 and MDA-MB-231) and drug resistant cell lines (LCC6/P-gp and MCF-7/1B1). All of these compounds were found to have selective inhibition towards CYP1B1 and the most potent two possessed single-digit nanomolar CYP1B1 potency. In addition, some of them showed promising cytotoxic activities not only against wild type cells, but also against drug resistant cells at low micromolar concentrations. More importantly, these multi-functional compounds may surmount drug-drug interactions that frequently occur during the combination of CYP1B1/P-gp inhibitors and anticancer drugs to overcome drug resistance. This study may provide a good starting point for the further development of more potent multi-functional agents with CYP1B1 inhibitory activity and cytotoxic potency in cancer prevention and treatment.
RESUMO
Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure-activity relationships of these compounds.