Taxane resistance in castration-resistant prostate cancer: mechanisms and therapeutic strategies

Despite its good initial response and significant survival benefit in patients with castration-resistant prostate cancer (CRPC), taxane therapy inevitably encounters drug resistance in all patients. Deep understandings of taxane resistant mechanisms can significantly facilitate the development of new therapeutic strategies to overcome taxane resistance and improve CRPC patient survival. Multiple pathways of resistance have been identified as potentially crucial areas of intervention. First, taxane resistant tumor cells typically have mutated microtubule binding sites, varying tubulin isotype expression, and upregulation of efflux transporters. These mechanisms contribute to reducing binding affinity and availability of taxanes. Second, taxane resistant tumors have increased stem cell like characteristics, indicating higher potential for further mutation in response to therapy. Third, the androgen receptor pathway is instrumental in the proliferation of CRPC and multiple hypotheses leading to this pathway reactivation have been reported. The connection of this pathway to the AKT pathway has received significant attention due to the upregulation of phosphorylated AKT in CRPC. This review highlights recent advances in elucidating taxane resistant mechanisms and summarizes potential therapeutic strategies for improved treatment of CRPC.

Research Progress of ABC Membrane Transporters and Their Regulation in Tumor Drug Resistance and New Mechanism of Detoxification / 中国药学杂志

Multidrug resistance of tumor cells is a material cause of chemotherapy failure, and the overexpression of adenosine triphosphate-binding cassette(ABC) membrane transporters is an important factor in multidrug resistance. Significant progress has been made in reversing multidrug resistance by reducing the expression of drug transporters on tumor cells; inspired by the mechanism of multidrug resistance, speeding up the efflux of poisons by increasing the expression of drug transporters is attracting more and more attention. In this review, We summarized the research progress on mechanism of membrane transp-orters in drug resistance in recent years, and new mechanism of detoxification based on these theories.

Progress of the drug efflux mechanisms underlying fungi multidrug resistance / 药学实践杂志

The multidrug resistance (MDR) ,characterized by the simultaneous acquisition of resistance to chemically and structurally different drugs ,has caused antifungal treatment failure .This review focused on recent progresses in under-standing of the multidrug resisitance associated drug efflux transporter superfamily in Saccharomyces cerevisiae ,the opportun-istic fungal pathogens Candida albicans ,Candida glabrata ,and Aspergillus fumigates ,along with the mechanisms underly-ing efflux pump and the regulatory networks involved .Investigation of these mechanisms and their impact on drug resistance may lead to strategies to overcome fungal multidrug resistance and improvement of drug efficacy .

Involvement of NRF2 Signaling in Doxorubicin Resistance of Cancer Stem Cell-Enriched Colonospheres

Cancer stem cells (CSCs) are a subset of tumor cells, which are characterized by resistance against chemotherapy and environmental stress, and are known to cause tumor relapse after therapy. A number of molecular mechanisms underlie the chemoresistance of CSCs, including high expression levels of drug efflux transporters. We investigated the role of the antioxidant transcription factor NF-E2-related factor 2 (NRF2) in chemoresistance development, using a CSC-enriched colonosphere system. HCT116 colonospheres were more resistant to doxorubicin-induced cell death and expressed higher levels of drug efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) compared to HCT116 monolayers. Notably, levels of NRF2 and expression of its target genes were substantially elevated in colonospheres, and these increases were linked to doxorubicin resistance. When NRF2 expression was silenced in colonospheres, Pgp and BCRP expression was downregulated, and doxorubicin resistance was diminished. Collectively, these results indicate that NRF2 activation contributes to chemoresistance acquisition in CSC-enriched colonospheres through the upregulation of drug efflux transporters.

Advances in study on compatibility of licorice and its mechanism of detoxification based on pharmacokinetics / 中草药

Licorice is one of Chinese materia medica (CMM) widely used in Chinese medicinal formulae as assistant and guiding medicines, it plays a role in restricting the main drug's toxicity and moderating the property of herbs. Licorice is regarded as a herb that can moderate the property of each herb and remove the hundreds of toxicants. Based on the above characteristics, toxic CMM is always used with licorice. However, the mechanism of the compatibility of licorice is not very clear. It is a good way for us to understand the principle and law of the compatibility of licorice, and to know the relationship between the process and compatibility detoxifying mechanism of licorice through studying on how the licorice has an effect on intracorporal process of the main components in the toxic CMM. The paper mainly summarizes the study on the pharmacokinetics of toxic CMM by compatibility of licorice and its mechanism of pharmacokinetic detoxification.

Mechanisms and significance of fungicide resistance / Mecanismos e significância da resistência a fungicidas

In this review article, we show that occurrence of fungicide resistance is one of the most important issues in modern agriculture. Fungicide resistance may be due to mutations of genes encoding fungicide targets (qualitative fungicide resistance) or to different mechanisms that are induced by sub-lethal fungicide stress. These mechanisms result in different and varying levels of resistance (quantitative fungicide resistance). We discuss whether or not extensive use of fungicides in agricultural environments is related to the occurrence of fungicide resistance in clinical environments. Furthermore, we provide recommendations of how development of fungicide resistant pathogen populations may be prevented or delayed.

A ocorrência de resistência a fungicidas é uma das mais importantes conseqüências da agricultura moderna. Este fato pode ser resultado de mutações em genes codificadores de resistência a fungicidas (resistência quantitativa) ou a diferentes mecanismos que são induzidos por stresse devido a doses subletais dos produtos utilizados. Estes mecanismos produzem diferentes e variados níveis de resistência (resistência quantitativa). Também é discutido se o uso extensivo de fungicidas em ambientes agricultáveis é relacionado ou não com a ocorrência de resistência em ambientes clínicos. Além disso, também são fornecidas recomendações de como prevenir ou mesmo retardar o desenvolvimento de resistência a fungicidas em patógenos.

Therapeutic carbamazepine (CBZ) and valproic acid (VPA) monitoring in children using saliva as a biologic fluid / Monitoramento terapêutico de carbamazepina e ácido valproico em saliva de crianças

OBJECTIVE: The aim of the study was to analyze retrospectively carbamazepine (CBZ) and valproic acid (VPA) salivary data collected from epileptic children during a 3-year period. METHODS: Saliva samples stimulated by citric acid were assayed by FPIA method. One hundred and three patients (aged 1-14 years) were in CBZ or VPA monotherapy or in CBZ-VPA combined therapy. RESULTS: VPA salivary levels were linearly related with daily dose, but a non-linear relationship was found for CBZ, in patients under monotherapy. VPA did not alter saliva CBZ concentration. Conversely, CBZ reduced VPA salivary levels. Non-responsive children displayed higher VPA concentrations. CBZ levels in uncontrolled patients showed non-significant difference in relation with controlled subjects even though their daily doses were higher. CONCLUSION: Citric acid stimulated saliva is reliable enough to perform therapeutic drug monitoring. Saliva drug levels in non-responsive patients would be explained according to the generalized efflux transporter overexpression hypothesis.

OBJETIVO: O objetivo deste estudo foi avaliar retrospectivamente por 3 anos a partir de dados salivares, as terapias com carbamacepina (CBZ) e ácido valproico (VPA) em pacientes pediátricos. MÉTODOS: Foram avaliadas amostras de saliva estimuladas com ácido cítrico por método FPIA em 103 pacientes (idades 1-14 anos) em monoterapia com CBZ ou VPA ou terapia combinada CBZ-VPA. RESULTADOS: Níveis salivares de VPA se relacionaram linearmente com a dose diária, e a relação não linear foi encontrada em pacientes com CBZ. VPA não alterou as concentrações salivares de CBZ, porém a CBZ reduziu os níveis salivares de VPA em pacientes com terapia combinada. Pacientes refratários apresentaram altas concentrações de VPA. Os níveis de CBZ em pacientes não controlados não apresentaram diferenças significativas em relação aos pacientes controlados quando as doses diárias foram mais elevadas. CONCLUSÃO: Saliva estimulada com ácido cítrico é adequada para o monitoramento terapêutico. Níveis da droga na saliva em pacientes que não responderam ao tratamento pode ser explicado pelo transporte de efluxo generalizado.