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ABSTRACT Background: Latent HIV-1 is a major hurdle in obtaining HIV-1 sustained virological remission (SVR). Here we explored histone deacetylation inhibition property of nicotinamide (NAM; n = 17) for the first time in comparison to a combination of methyltransferase inhibitors (MTIs; Chaetocin and BIX01294; n = 25) to reactivate latent HIV ex vivo in CD8-depleted PBMCs from antiretroviral treated aviremic individuals. Results: NAM reactivated HIV-1 from 13/17 (76.4%) samples compared to 20/25 (80.0%) using MTIs with mean viral load (VLs) of 4.32 and 3.22 log10 RNA copies/mL, respectively (p = 0.004). Mean purging time after NAM and MTIs stimulation was 5.1 and 6.75 days, respectively (p = 0.73). Viral purging in autologous cultures exhibited blunted HIV recovery with fluctuating VLs followed by a complete viral extinction when expanded in allogenic system. Electron microscopy from five supernatants revealed anomalous viral particles, with lack of complete viral genomes when characterized by ultradeep sequencing through metagenomics approach (n = 4). Conclusion: NAM alone was more potent HIV-1 activator than combination of MTIs, with potential of clinical use.
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Young Adult , Quinazolines/pharmacology , Azepines/pharmacology , Virus Activation/drug effects , HIV Infections/virology , HIV-1/drug effects , Niacinamide/pharmacology , Methyltransferases/antagonists & inhibitors , Piperazines/pharmacology , Leukocytes, Mononuclear/virology , CD4-Positive T-Lymphocytes , Gene Expression Regulation, Viral , Virus Latency , Viral Load/drug effects , Viral Tropism/drug effectsABSTRACT
Multidrug resistance (MDR) is a major cause of cancer chemotherapy failure, and it is important to develop suitable reversal agents to overcome MDR. A majority of chemical reversal agents have acceptable reversal effects. However, the toxicity and adverse reactions associated with these agents restricts their clinical use. Chinese medicines (CMs) have lower toxicities and adverse reactions and are associated with multiple components, multiple targets and reduced toxicity. CMs have several advantages and could reverse MDR, decrease drug dosage, enhance patient compliance and increase efficacy. This review summarizes the current progress of CM reversal agents..
Subject(s)
Humans , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drugs, Chinese Herbal , Pharmacology , Plant Extracts , Pharmacology , ResearchABSTRACT
A new type of direct oral anticoagulants (DOACs) was approved for the prevention of thrombotic stroke in patients with nonvalvular atrial fibrillation and for treatment of venous thrombosis (VTE)/pulmonary infarction (PE) in 2010. Compared with the traditional oral anticoagulant vitamin K antagonist (VKA), DOACs have similar anticoagulant effect, better safety, easier administration and less intracranial hemorrhage, but it may increase the risk of gastrointestinal bleeding. As the half-life of DOACs is short, most gastrointestinal bleeding caused by DOACs does not require special treatment, but in rare situations, such as life-threatening bleeding or emergency surgery, DOACs reversal agent was needed to resist the anticoagulation of DOAC. In this review, we summarized the current status of DOACs, incidence of DOACs associated gastrointestinal bleeding, related prophylaxis and DOACs-specific reversal agents.
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Leukemia is a common malignant tumor in blood system, and it is one of the 10 high incidence malignant tumors in China. The main reason related to the failure of chemotherapy in leukemia is multidrug resistance (MDR). Chemical reversal agents often have the side effects and the mechanisms of chemical reversal agents are single, which restricts its clinical application. With efficiency, low-level toxicity, and multi-target points, Chinese materia medica shows its unique advantages in reversing MDR of leukemia. This paper summarizes the MDR mechanisms of leukemia and reversal agents in Chinese medicine in order to find more Chinese medicine to reverse leukemia.
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Cancer has become the leading cause of death. Chemotherapy with comprehensive treatment is the main treatment for cancer patients. Multi-drug resistance (MDR)is one of the main obstacles limiting the efficacy of clinical chemotherapy treatment for tumors. Consequently, searching for highly effective and lowly toxic MDR reversal agents is an mportant work with regard to cancer drug development. Traditional Chinese medicines (TCM)and natural medicines, which have rich resouce, little drug side effects and varied chemical constituents are mportant sources for new MDR reversal agents. In this paper, the advances of MDR reversal agents from TCM and natural medicine since 2000 are reviewed.
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P-glycoprotein(P-gp) is a multi-drug efflux transporter that plays a significant role in governing the bioavailability of various anti-cancer drugs. P-gp transporter impedes the permeability of drugs through physiological barriers resulting in limited pharmacological response. Modulation of this efflux transporter by various traditional "chemosensitizers" forms a distinctive approach in improving pharmacokinetics and conquering drug resistance. This review summarizes the recent advances in structural information of P-gp interactions with investigated ligands and new strategies to improve the poor efficiency in chemotherapy.
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Multidrug resistance (MDR) is the phenomenon observed in tumor cells that describes the simultaneous emergence of cellular resistance to the cytotoxic attack by structurally and mechanism unrelated chemotherapeutic drugs. The mdr 1 gene was sufficient to confer the MDR phenotype, including the expression of the P Glycoprotein (P Gp). P Gp appears to play an important role in tumor cells by acting as an energy dependent efflux pump to remove various drugs from the cell before they have a chance to exert their cytotoxic effects. It is generally accepted that reversal or inhibition of P Gp function in tumor cells is an important way for modulating MDR. It has been demonstrated in the laboratory that MDR mediated by the P Gp may be modulated by a wide variety of compounds. These compounds , which include verapamil and cyclosporin, generally have little or no effect by themselves on the tumor cells, but when used in conjunction with antineoplastic agents, they decrease, and in some instances eliminate, MDR. This paper will introduce some new reversal agents and discuss their physical and chemical characteration and others.
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The multi drug resistance(MDR) of tumor cells has become a difficult problem in the chemotherapy of tumor, meanwhile, the mechanism of MDR are various:relevant drugs with reversal effects have been discovered. This review will provide the most impossible mechanisms of MDR and some prospecting reversal drugs.