RESUMEN
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated from combustion of carbon-based matter. Upon ingestion, these molecules can be bioactivated by cytochrome P450 monooxygenases to oxidized toxic metabolites. Some of these metabolites are potent carcinogens that can form irreversible adducts with DNA and other biological macromolecules. Conjugative enzymes, such as glutathione S-transferases or UDP-glucuronosyltransferases, are responsible for the detoxification and/or facilitate the elimination of these carcinogens. While responses to PAH exposures have been extensively studied for the bioactivating cytochrome P450 enzymes, much less is known regarding the response of glutathione S-transferases in mammalian systems. In this study, we investigated the expression and activity responses of murine hepatic glutathione S-transferases to benzo[ a]pyrene exposure using global proteomics and activity-based protein profiling for chemoproteomics, respectively. Using this approach, we identified several enzymes exhibiting increased activity including GSTA2, M1, M2, M4, M6, and P1. The activity of one GST enzyme, GSTA4, was found to be downregulated with increasing B[ a]P dose. Activity responses of several of these enzymes were identified as being expression-independent when comparing global and activity-based data sets, possibly alluding to as of yet unknown regulatory post-translational mechanisms.
Asunto(s)
Benzo(a)pireno/farmacología , Glutatión Transferasa/metabolismo , Animales , Benzo(a)pireno/química , Inducción Enzimática/efectos de los fármacos , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos , Sondas Moleculares/química , Estructura Molecular , Proteómica , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismoRESUMEN
The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/terapia , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/prevención & control , Femenino , Humanos , Neoplasias Inflamatorias de la Mama/tratamiento farmacológico , Neoplasias Inflamatorias de la Mama/metabolismo , Neoplasias Inflamatorias de la Mama/prevención & control , Neoplasias Inflamatorias de la Mama/terapia , Terapia Molecular Dirigida , Transducción de SeñalRESUMEN
Natural products with biodiversity and chemical variations present a rich source for the discovery and development of new therapeutic and preventive drugs. Bioactive components derived from natural medicines including traditional Chinese medicine have been widely used for the screening of effective and safe anticancer drugs. Meanwhile, the investigation on mechanism of action (MOA) of natural bioactive components has a critical role in identifying and validating new molecular targets of those anticancer agents. Considering the high complexity of pharmacodynamic (PD) and pharmacokinetic (PK) characteristics of natural product anticancer agents, there are several major challenges in understanding mechanisms of action in vitro and in vivo for these agents. The recent rapid progress made in molecular and cell biology, genetics and genomics, and translational medicine, preclinical investigations provides an impetus for a better understanding of mechanisms of action and structure-activity relationships (SAR) of natural products. In addition, the simultaneous evaluation of PD-PK characterizations would allow a full assessment of the safety, efficacy, and indication of natural product anticancer drugs in various regimens and in various clinical settings. In this review, we provide a brief summary for recent advances in translational pharmacology, focusing on target validation and PK-PD, MOA, and SAR. Several examples for clinically used agents, and cancer preventive agents and therapeutic agents under preclinical and clinical development are used to illustrate the importance of such translational research and challenges we are facing.
Asunto(s)
Antineoplásicos/uso terapéutico , Productos Biológicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Fitoterapia , Animales , Humanos , Neoplasias/metabolismo , Investigación Biomédica TraslacionalRESUMEN
MicroRNAs (miRNAs) are endogenous small non-coding RNAs that regulate gene expression by binding to the 3´untranslated region of target mRNA, resulting in posttranscriptional gene silencing via mRNA degradation or translation inhibition. miRNAs are involved in many biological processes including carcinogenesis. They can act as oncogenes or tumor suppressors and their aberrant expressions are intimately linked with cancer development and progression. Therefore, miRNAs have been utilized as potential biomarkers for cancer diagnosis, prognosis, as well as cancer therapeutic targets. Recently, it has been demonstrated that dietary and natural chemopreventive agents exert their anticancer activities through the regulation of one or more miRNAs. In addition to expounding the latest findings of miRNAs in cancer, this review also discusses the recent efforts on the translational research of miRNAs, with an emphasis on natural products in the treatment of cancer.