RESUMEN
Epithelial-mesenchymal transition (EMT) is a complicated molecular process that governs cellular shape and function changes throughout tissue development and embryogenesis. In addition, EMT contributes to the development and spread of tumors. Expanding and degrading the surrounding microenvironment, cells undergoing EMT move away from the main location. On the basis of the expression of fibroblast-specific protein-1 (FSP1), fibroblast growth factor (FGF), collagen, and smooth muscle actin (-SMA), the mesenchymal phenotype exhibited in fibroblasts is crucial for promoting EMT. While EMT is not entirely reliant on its regulators like ZEB1/2, Twist, and Snail proteins, investigation of upstream signaling (like EGF, TGF-ß, Wnt) is required to get a more thorough understanding of tumor EMT. Throughout numerous cancers, connections between tumor epithelial and fibroblast cells that influence tumor growth have been found. The significance of cellular crosstalk stems from the fact that these events affect therapeutic response and disease prognosis. This study examines how classical EMT signals emanating from various cancer cells interfere to tumor metastasis, treatment resistance, and tumor recurrence.
Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias , Humanos , Transición Epitelial-Mesenquimal/fisiología , Neoplasias/metabolismo , Transducción de Señal , Fenotipo , Resistencia a Medicamentos , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC4) and estradiol 17 ß-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Resistencia a Múltiples Medicamentos/genética , Mesilato de Imatinib/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are a matter of concern for public health. Antibiotic resistance plays an important role in driving C. difficile epidemiology. Emergence of new types is often associated with the emergence of new resistances, and most of the epidemic C. difficile clinical isolates is currently resistant to multiple antibiotics. In particular, it is to worth to note the recent identification of strains with reduced susceptibility to the first-line antibiotics for CDI treatment and/or for relapsing infections. Antibiotic resistance in C. difficile has a multifactorial nature. Acquisition of genetic elements and alterations of the antibiotic target sites, as well as other factors, such as variations in the metabolic pathways or biofilm production, contribute to the survival of this pathogen in the presence of antibiotics. Different transfer mechanisms facilitate the spread of mobile elements among C. difficile strains and between C. difficile and other species. Furthermore, data indicate that both genetic elements and alterations in the antibiotic targets can be maintained in C. difficile regardless of the burden imposed on fitness, and therefore resistances may persist in C. difficile population in absence of antibiotic selective pressure.
Asunto(s)
Clostridioides difficile , Clostridioides , Clostridioides difficile/genética , Farmacorresistencia Microbiana/genética , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , BiopelículasRESUMEN
Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed a beneficial approach for a quick and cost-effective drug discovery process by skipping preclinical, Phase 1 trials and pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), were studied for their potential application in different diseases, especially in cancer therapy. Fluoxetine (FLX) is one of the most prescribed psychotropic agents from the SSRIs class for the treatment of several neuropsychiatric disorders with a favorable safety profile. FLX exhibited different oncolytic effects via mechanisms distinct from its main serotonergic activity. Taking advantage of its ability to rapidly penetrate the blood-brain barrier, FLX could be particularly useful in brain tumors. This was proved by different in vitro and in vivo experiments using FLX as a monotherapy or combination with temozolomide (TMZ) or radiotherapy. In this review of the literature, we summarize the potential pleiotropic oncolytic roles of FLX against different cancers, highlighting the multifaceted activities of FLX and its ability to interrupt cancer proliferation via several molecular mechanisms and even surmount multidrug resistance (MDR). We elaborated on the successful synergistic combinations such as FXR/temozolomide and FXR/raloxifene for the treatment of glioblastoma and breast cancer, respectively. We showcased beneficial pharmaceutical trials to load FLX onto carriers to enhance its safety and efficacy on cancer cells. This is the first review article extensively summarizing all previous FLX repurposing studies for the management of cancer.
Asunto(s)
Reposicionamiento de Medicamentos , Fluoxetina , Humanos , Reposicionamiento de Medicamentos/métodos , Fluoxetina/uso terapéutico , Fluoxetina/farmacología , Animales , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Psicotrópicos/uso terapéutico , Psicotrópicos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Multidrug resistance is a serious problem in modern medicine and the reason for the failure of various therapies. A particularly important problem is the occurrence of multidrug resistance in cancer therapies which affects many cancer patients. Observations on the effect of metformin-a well-known hypoglycemic drug used in the treatment of type 2 diabetes-on cancer cells indicate the possibility of an interaction of this substance with drugs already used and, as a result, an increase in the sensitivity of cancer cells to cytostatics. The aim of this study was to evaluate the effect of metformin on the occurrence of multidrug resistance of breast cancer cells. The MCF-7-sensitive cell line and the MCF-7/DX cytostatic-resistant cell line were used for this study. WST-1 and LDH assays were used to evaluate the effects of metformin and doxorubicin on cell proliferation and viability. The effect of metformin on increasing the sensitivity of MCF-7 and MCF-7/DX cells to doxorubicin was evaluated in an MDR test. The participation of metformin in increasing the sensitivity of resistant cells to the effect of the cytostatic (doxorubicin) has been demonstrated.
Asunto(s)
Neoplasias de la Mama , Proliferación Celular , Citostáticos , Doxorrubicina , Resistencia a Antineoplásicos , Metformina , Humanos , Metformina/farmacología , Células MCF-7 , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Doxorrubicina/farmacología , Femenino , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Supervivencia Celular/efectos de los fármacos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Hipoglucemiantes/farmacologíaRESUMEN
Two new phenylspirodrimanes, stachybotrins K and L (1 and 2), together with eight known analogues (3-10), were isolated from deep-sea-derived Stachybotrys sp. MCCC 3A00409. Their structures were determined by extensive NMR data and mass spectroscopic analysis. Absolute configurations of new compounds were determined through a comparison of their circular dichroism (CD) spectra with other reported compounds. The possible reversal effects of all compounds were assayed in the resistant cancer cell lines. Stachybotrysin B (8) can reverse multidrug resistance (MDR) in ABCB1-overexpression cells (KBv200, Hela/VCR) at the non-cytotoxic concentration. Doxorubicin accumulation assay and molecular-docking analysis reveal that the mechanism of its reversal MDR effect may be related to the increase in the intracellular concentration of substrate anticancer drugs.
Asunto(s)
Stachybotrys , Humanos , Bioensayo , Dicroismo Circular , Células HeLa , Resistencia a Múltiples MedicamentosRESUMEN
P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic-polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy - MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.
Asunto(s)
Infección por el Virus Zika , Virus Zika , Embarazo , Femenino , Humanos , Ratones , Animales , Placenta/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Distribución Tisular , Proteínas de Neoplasias/genética , Resistencia a Múltiples Medicamentos , Proteínas de Transporte de Membrana/metabolismoRESUMEN
Modern clinical therapy of chronic myeloid leukemia (CML) with TKIs is highly efficacious in most CML patients, while it is not remedial and generally confined due to intolerance or resistance. CML is currently considered a severe disease. Interestingly, stem cell transplantation in the past decade was an attractive clinical therapeutic option in CML patients, but it is not successful due to independently more death rates in older patients. So, the targeting of BCR::ABL oncoprotein is extensively used to enhance the reduction in a higher percentage of CML patients by tyrosine kinase inhibitors (TKIs). However, resistance or intolerance responses to these inhibitors are responsible for future deterioration and further development of disease. At this point, the clinical treatment of CML is a major challenge, and the lack of molecular responses to TKIs are not succeeded with chemotherapy alone. So, the considerable efficacious clinical necessities remain unmet. Therefore, continuous efforts are needed to explore new potential treatment strategies with an increasing understanding of CML biology. Therefore, this review deals with the investigation of TKI treatment with interferon, chemotherapy (Hydroxyurea, Homoharringtonine, Omacetaxine, Cytarabine), and several other new TKIs under beneficial clinical trials. Additionally, the approaches towards TKIs-resistant or intolerant CML cells where the respective signaling pathway gets up-regulated are also targeted with its inhibitor. This review presents evidence that new TKIs under clinical and pre-clinical trials may improve the chemotherapy of CML.
Asunto(s)
Resistencia a Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Anciano , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Transducción de Señal , Inhibidores de Proteínas Quinasas/farmacología , Proteínas de Fusión bcr-abl/uso terapéuticoRESUMEN
Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case-control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). CONCLUSIONS: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. TRIAL REGISTRATION: Deutsches Register Klinischer Studien ( https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817 ), DRKS00023817, 2020-09-08. WHAT IS KNOWN: â¢Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). â¢Choice of treatment regimen and monitoring of side effects. WHAT IS NEW: â¢Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. â¢The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.
Asunto(s)
Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis , Humanos , Niño , Estudios Retrospectivos , Estudios de Casos y Controles , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/epidemiología , Tuberculosis/tratamiento farmacológico , Factores de Riesgo , Enfermedades Raras , Antituberculosos/uso terapéuticoRESUMEN
Integrin-linked kinase (ILK) is a multifunctional molecular actor in cell-matrix interactions, cell adhesion, and anchorage-dependent cell growth. It combines functions of a signal transductor and a scaffold protein through its interaction with integrins, then facilitating further protein recruitment within the ILK-PINCH-Parvin complex. ILK is involved in crucial cellular processes including proliferation, survival, differentiation, migration, invasion, and angiogenesis, which reflects on systemic changes in the kidney, heart, muscle, skin, and vascular system, also during the embryonal development. Dysfunction of ILK underlies the pathogenesis of various diseases, including the pro-oncogenic activity in tumorigenesis. ILK localizes mostly to the cell membrane and remains an important component of focal adhesion. We do know much about ILK but a lot still remains either uncovered or unclear. Although it was initially classified as a serine/threonine-protein kinase, its catalytical activity is now questioned due to structural and functional issues, leaving the exact molecular mechanism of signal transduction by ILK unsolved. While it is known that the three isoforms of ILK vary in length, the presence of crucial domains, and modification sites, most of the research tends to focus on the main isoform of this protein while the issue of functional differences of ILK2 and ILK3 still awaits clarification. The activity of ILK is regulated on the transcriptional, protein, and post-transcriptional levels. The crucial role of phosphorylation and ubiquitylation has been investigated, but the functions of the vast majority of modifications are still unknown. In the light of all those open issues, here we present an extensive literature survey covering a wide spectrum of latest findings as well as a past-to-present view on controversies regarding ILK, finishing with pointing out some open questions to be resolved by further research.
Asunto(s)
Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neovascularización Patológica/genética , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/genética , Animales , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Invasividad Neoplásica , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias , Selenio , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Neoplasias/tratamiento farmacológico , Especies Reactivas de Oxígeno , Selenio/química , Selenio/farmacología , Selenio/uso terapéutico , Telurio/química , Telurio/farmacología , Telurio/uso terapéuticoRESUMEN
BACKGROUND: HMGB1 (high mobility group box B-1) exhibits crucial role in tumor genesis and development, including lung cancer. Whereas, more HMGB1-related details in non-small cell lung cancer (NSCLC) are still largely unclear. METHODS: The HMGB1 and inflammatory factors in malignant (MPE) and non-malignant pleural effusion (BPE) were determined by ELISA. Additionally, qRT-PCR, western blot, or immunohistochemistry were used to determine HMGB1, drug-resistant and apoptotic proteins' expressions in NSCLC A549, A549-DDP cell lines, and xenograft model. Cell viability, migration/ invasion, and apoptosis were analyzed using MTT, Transwell, and flow cytometry assays, respectively. RESULTS: Inflammatory factors and HMGB1 expressions in MPE were significantly higher than BPE of NSCLC. Compared with preoperative and adjacent tissues, significantly higher HMGB1, drug-resistant protein, and anti-apoptotic protein expressions were observed in recurrent tissues. Overexpressed HMGB1 induced NSCLC cells to exhibit stronger aggressive, proliferative, and drug-resistant features. The related abilities were reversed when HMGB1 was interfered. Overexpressed HMGB1 showed a similar co-localization with drug resistant protein P-gp in cytoplasm in xenograft model, while low HMGB1 expression localized in cell nucleus. CONCLUSIONS: HMGB1 overexpression significantly promoted the malignant progression and cisplatin resistance of NSCLC in vitro and in vivo.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proteína HMGB1 , Neoplasias Pulmonares , MicroARNs , Humanos , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MicroARNs/metabolismo , AnimalesRESUMEN
In tumors, the multi drug resistance phenomenon may occur through the efflux of chemotherapeutic drugs out of cancer cells, impeding their accumulation, and eventually reducing their toxicity. This process is mediated by transporters overexpressed in the plasma membranes of tumor cells, among which is the P-glycoprotein/multidrug resistance 1/ATP-binding cassette B1 (P-gp/MDR1/ABCB1). The aim of this study was to explore the effect of a new molecule, called AIF-1, on ABCB1 activity. In a cellular model of non-small cell lung cancer (NSCLC), AIF-1 significantly inhibited ABCB1 activity, which was evaluated by the fluorimetric measurement of the intracellular accumulation of calcein. AIF-1 also significantly increased the intracellular content of doxorubicin, which was evaluated by confocal microscopy and LC-MS/MS analysis. This effect translated to higher cytotoxicity of doxorubicin and reduced cellular proliferation. Finally, in a murine xenograft model, the tumor volume increased by 267% and 148% on average in mice treated with vehicle and doxorubicin alone, respectively. After the co-administration of doxorubicin with AIF-1, tumor volume increased by only 13.4%. In conclusion, these results suggest enhancement of the efficacy of the chemotherapeutic drug doxorubicin by AIF-1, laying the basis for the future development of new ABCB1 inhibitors for tumor treatment.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cromatografía Liquida , Resistencia a Antineoplásicos , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Espectrometría de Masas en Tándem , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Doxorrubicina/metabolismoRESUMEN
The discovery of the first ATP-binding cassette (ABC) transporter, whose overexpression in cancer cells is responsible for exporting anticancer drugs out of tumor cells, initiated enormous efforts to overcome tumor cell multidrug resistance (MDR) by inhibition of ABC-transporter. Because of its many physiological functions, diverse studies have been conducted on the mechanism, function and regulation of this important group of transmembrane transport proteins. In this review, we will focus on the structural aspects of this transporter superfamily. Since the resolution revolution of electron microscope, experimentally solved structures increased rapidly. A summary of the structures available and an overview of recent structure-based studies are provided. More specifically, the artificial intelligence (AI)-based predictions from AlphaFold-2 will be discussed.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Transportadoras de Casetes de Unión a ATP/metabolismo , Inteligencia Artificial , Resistencia a Antineoplásicos , Resistencia a Múltiples Medicamentos , Antineoplásicos/química , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1/P-gp) is a major cause of cancer chemotherapy failure, but the regulation mechanisms are largely unknown. METHODS: Based on single gene knockout, we studied the regulation of CDK6-PI3K axis on ABCB1-mediated MDR in human cancer cells. CRISPR/Cas9 technique was performed in KB-C2 cells to knockout cdk6 or cdk4 gene. Western blot, RT-PCR and transcriptome analysis were performed to investigate target gene deletion and expression of critical signaling factors. The effect of cdk4 or cdk6 deficiency on cell apoptosis and the cell cycle was analyzed using flow cytometry. In vivo studies were performed to study the sensitivity of KB-C2 tumors to doxorubicin, tumor growth and metastasis. RESULTS: Deficiency of cdk6 led to remarkable downregulation of ABCB1 expression and reversal of ABCB1-mediated MDR. Transcriptomic analysis revealed that CDK6 knockout regulated a series of signaling factors, among them, PI3K 110α and 110ß, KRAS and MAPK10 were downregulated, and FOS-promoting cell autophagy and CXCL1-regulating multiple factors were upregulated. Notably, PI3K 110α/110ß deficiency in-return downregulated CDK6 and the CDK6-PI3K axis synergizes in regulating ABCB1 expression, which strengthened the regulation of ABCB1 over single regulation by either CDK6 or PI3K 110α/110ß. High frequency of alternative splicing (AS) of premature ABCB1 mRNA induced by CDK6, CDK4 or PI3K 110α/110ß level change was confirmed to alter the ABCB1 level, among them 10 common skipped exon (SE) events were found. In vivo experiments demonstrated that loss of cdk6 remarkably increased the sensitivity of KB-C2 tumors to doxorubicin by increasing drug accumulation of the tumors, resulting in remarkable inhibition of tumor growth and metastasis, as well as KB-C2 survival in the nude mice. CONCLUSIONS: CDK6-PI3K as a new target signaling axis to reverse ABCB1-mediated MDR is reported for the first time in cancers. Pathways leading to inhibition of cancer cell proliferation were revealed to be accompanied by CDK6 deficiency.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Antineoplásicos , Quinasa 6 Dependiente de la Ciclina , Neoplasias , Fosfatidilinositol 3-Quinasas , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/genética , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Humanos , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
One of the primary causes of attenuated or loss of efficacy of cancer chemotherapy is the emergence of multidrug resistance (MDR). Numerous studies have been published regarding potential approaches to reverse resistance to taxanes, including paclitaxel (PTX) and docetaxel, which represent one of the most important classes of anticancer drugs. Since 1984, following the FDA approval of paclitaxel for the treatment of advanced ovarian carcinoma, taxanes have been extensively used as drugs that target tumor microtubules. Taxanes, have been shown to affect an array of oncogenic signaling pathways and have potent cytotoxic efficacy. However, the clinical success of these drugs has been restricted by the emergence of cancer cell resistance, primarily caused by the overexpression of MDR efflux transporters or by microtubule alterations. In vitro and in vivo studies indicate that the mechanisms underlying the resistance to PTX and docetaxel are primarily due to alterations in α-tubulin and ß-tubulin. Moreover, resistance to PTX and docetaxel results from: 1) alterations in microtubule-protein interactions, including microtubule-associated protein 4, stathmin, centriole, cilia, spindle-associated protein, and kinesins; 2) alterations in the expression and activity of multidrug efflux transporters of the ABC superfamily including P-glycoprotein (P-gp/ABCB1); 3) overexpression of anti-apoptotic proteins or inhibition of apoptotic proteins and tumor-suppressor proteins, as well as 4) modulation of signal transduction pathways associated with the activity of several cytokines, chemokines and transcription factors. In this review, we discuss the abovementioned molecular mechanisms and their role in mediating cancer chemoresistance to PTX and docetaxel. We provide a detailed analysis of both in vitro and in vivo experimental data and describe the application of these findings to therapeutic practice. The current review also discusses the efficacy of different pharmacological modulations to achieve reversal of PTX resistance. The therapeutic roles of several novel compounds, as well as herbal formulations, are also discussed. Among them, many structural derivatives had efficacy against the MDR phenotype by either suppressing MDR or increasing the cytotoxic efficacy compared to the parental drugs, or both. Natural products functioning as MDR chemosensitizers offer novel treatment strategies in patients with chemoresistant cancers by attenuating MDR and increasing chemotherapy efficacy. We broadly discuss the roles of inhibitors of P-gp and other efflux pumps, in the reversal of PTX and docetaxel resistance in cancer cells and the significance of using a nanomedicine delivery system in this context. Thus, a better understanding of the molecular mechanisms mediating the reversal of drug resistance, combined with drug efficacy and the application of target-based inhibition or specific drug delivery, could signal a new era in modern medicine that would limit the pathological consequences of MDR in cancer patients.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Taxoides/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Hidrocarburos Aromáticos con Puentes , Línea Celular Tumoral , Portadores de Fármacos , Resistencia a Antineoplásicos/genética , Genes Supresores de Tumor/efectos de los fármacos , Genes Supresores de Tumor/fisiología , Humanos , Microtúbulos/fisiología , Nanopartículas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Tubulina (Proteína)/efectos de los fármacosRESUMEN
Two new series of symmetric (1a-h) and asymmetric (2a-l) 1,4-DHP derivatives were designed, synthesised, and evaluated as anticancer agents. In vitro anticancer screening of target compounds via National cancer institute "NCI" revealed that analogues 1g, 2e, and 2l demonstrated antiproliferative action with mean growth inhibition percentage "GI%" = 41, 28, and 64, respectively. The reversal doxorubicin (DOX) effects of compounds 1g, 2e, and 2l were examined and illustrated better cytotoxic activity with IC50 =1.12, 3.64, and 3.57 µM, respectively. The most active anticancer analogues, 1g, 2e, and 2l, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), and Bruton's tyrosine kinase (BTK) inhibitory activities. Furthermore, the antimicrobial activity of target compounds was assessed against six different pathogens, followed by determining the minimum inhibitory concentration "MIC" values for the most active analogues. Molecular docking study was achieved to understand mode of interactions between selected inhibitors and different biological targets.
Asunto(s)
Antineoplásicos , Nitrilos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Dihidropiridinas , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
The extensive use of conventional antibiotics has led to the growing emergence of many resistant strains of pathogenic bacteria. Evidence suggests that cationic antimicrobial peptides (AMPs) have the greatest potential to serve as traditional antibiotic substitutes. Recent studies have also reported that certain AMPs have selective toxicity toward various types of cancer cells. The electrostatic attraction between the negatively charged membrane components and AMPs is believed to play a crucial role in the disruption of bacterial and cancer cell membranes. In the current study, we used a potent AMP called Pleurocidin (Ple) derived from winter flounder Pleuronectes americanus and its C-terminal-amidated derivative Pleurocidin-amide (Ple-a), and evaluated their antibacterial and anticancer activities. Our results indicated that both Ple and Ple-a exhibited significant antibacterial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, especially marine pathogens, with MIC values ranging from 0.25 to 32 µg/mL. These peptides are also potent against several multidrug-resistant (MDR) bacterial strains, with MIC values ranging from 2 to 256 µg/mL. When used in combination with certain antibiotics, they exhibited a synergistic effect against MDR E. coli. Ple and Ple-a also showed notable cytotoxicity toward various cancer cell lines, with IC50 values ranging from 11 to 340 µM, while normal mouse fibroblast 3T3 cells were less susceptible to these peptides. Ple-a was then selected to study its anticancer mechanism toward A549 human lung adenocarcinoma cells. Western blot analysis and confocal microscopy showed that Ple-a could inhibit autophagy of A549 cells, and induce apoptosis 48 h after treatment. Our findings provided support for the future application of Ple-a as potential therapeutic agent for bacterial infections and cancer treatment.
Asunto(s)
Lenguado , Amidas/farmacología , Animales , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Péptidos Antimicrobianos , Bacterias , Escherichia coli , Proteínas de Peces , Bacterias Gramnegativas , Bacterias Grampositivas , Humanos , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
Cancer is the leading cause of mortality worldwide. Various chemotherapeutic drugs have been extensively used for cancer treatment. However, current anticancer drugs cause severe side effects and induce resistance. Therefore, the development of novel and effective anticancer agents with minimal or no side effects is important. Notably, natural compounds have been highlighted as anticancer drugs. Among them, many researchers have focused on mushrooms that have biological activities, including antitumor activity. The aim of this review is to discuss the anticancer potential of different mushrooms and the underlying molecular mechanisms. We provide information regarding the current clinical status and possible modes of molecular actions of various mushrooms and mushroom-derived compounds. This review will help researchers and clinicians in designing evidence-based preclinical and clinical studies to test the anticancer potential of mushrooms and their active compounds in different types of cancers.
Asunto(s)
Agaricales , Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.