Pharmacological Reviews最新文献

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated cell growth. Genetic mutations can determine tumor onset by either augmenting cell division rates or restraining normal controls such as cell cycle arrest or apoptosis. As a result, tumor cells not only undergo uncontrolled cell division but also become compromised in their ability to exit the cell cycle accurately. Regulation of cell cycle progression is enabled by specific surveillance mechanisms known as cell cycle checkpoints, and aberrations in these signaling pathways often culminate in cancer. For instance, DNA damage checkpoints, which preclude the generation and augmentation of DNA damage in the G1, S, and G2 cell cycle phases, are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Notably, tumors have evolved to become dependent on checkpoints for their survival. For example, checkpoint pathways such as the DNA replication stress checkpoint and the mitotic checkpoint rarely undergo mutations and remain intact because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation leading to cell death. In this review, we initially focus on cell cycle control pathways and specific functions of checkpoint signaling involved in normal and cancer cells and then proceed to examine how cell cycle control and checkpoint mechanisms can provide new therapeutic windows that can be exploited for cancer therapy. SIGNIFICANCE STATEMENT: DNA damage checkpoints are often defective in cancer cells, allowing cell division in spite of the accumulation of genetic errors. Conversely, DNA replication stress and mitotic checkpoints rarely undergo mutations because any aberrant activity could result in irreparable damage or catastrophic chromosomal missegregation, leading to cancer cell death. This review focuses on the checkpoint signaling mechanisms involved in cancer cells and how an emerging understanding of these pathways can provide new therapeutic opportunities for cancer therapy.

Taking a historical perspective, we review the discovery, pharmacology, and clinical evaluation of the old and new anticoagulants that have been approved for clinical use. The drugs are discussed chronologically, starting in the 1880s, and progressing through to 2024. The innovations in technology used to develop novel anticoagulants came in fits and starts and reflected the advances in science and technology over these decades, whereas the shift from anecdote to evidence-based use of anticoagulants was delayed until the principles of epidemiology and biostatistics were introduced into clinical trial design and to the approval process. Hirudin, heparin, and vitamin K antagonists were discovered by chance, and were used clinically before their mechanism of action was elucidated and before their net clinical benefits were evaluated in randomized clinical trials. Subsequent anticoagulants were designed based on a better understanding of the structure and function of coagulation proteins, including antithrombin, thrombin, and factor Xa, and underwent more rigorous preclinical and clinical evaluation before regulatory approval. By simplifying oral anticoagulation, the direct oral anticoagulants have revolutionized anticoagulation care and have enhanced the uptake of anticoagulation, but bleeding has not been eliminated and there is a need for more effective and convenient anticoagulants for thrombosis triggered by the contact pathway of coagulation. The newly developed factor XIa and XIIa inhibitors have the potential to address these unmet clinical needs and are undergoing clinical evaluation for several indications. SIGNIFICANCE STATEMENT: Anticoagulant therapy is the cornerstone of treatment and prevention of thrombosis, which remains a leading cause of morbidity and mortality worldwide. Elucidation of the structure and function of coagulation enzymes, their cofactors, and inhibitors, coupled with advances in structure-based design led to the discovery of more convenient, safer, and more effective anticoagulants that have revolutionized the management of thrombotic disorders.

Ascorbic acid, the reduced form of vitamin C, is a ubiquitous small carbohydrate. Despite decades of focused research, new metabolic functions of this universal electron donor are still being discovered and add to the complexity of our view of vitamin C in human health. Although praised as an unsurpassed water-soluble antioxidant in plasma and cells, the most interesting functions of vitamin C seem to be its roles as specific electron donor in numerous biological reactions ranging from the well-known hydroxylation of proline to cofactor for the epigenetic master regulators ten-eleven translocation enzymes and Jumonji domain-containing histone-lysine demethylases. Some of these functions may have important implications for disease prevention and treatment and have spiked renewed interest in, eg, vitamin C's potential in cancer therapy. Moreover, some fundamental pharmacokinetic properties of vitamin C remain to be established including if other mechanisms than passive diffusion governs the efflux of ascorbate anions from the cell. Taken together, there still seems to be much to learn about the pharmacology of vitamin C and its role in health and disease. This review explores new avenues of vitamin C and integrates our present knowledge of its pharmacology. SIGNIFICANCE STATEMENT: Vitamin C is involved in multiple biological reactions of which most are essential to human health. Hundreds of millions of people are considered deficient in vitamin C according to accepted guidelines, but little is known about the long-term consequences. Although the complexity of vitamin C's physiology and pharmacology has been widely disregarded in clinical studies for decades, it seems clear that a deeper understanding of particularly its pharmacology holds the key to unravel and possibly exploit the potential of vitamin C in disease prevention and therapy.

Organic anion transporting polypeptides (OATPs) are membrane proteins that mediate the uptake of a wide range of substrates across the plasma membrane of various cells and tissues. They are classified into 6 subfamilies, OATP1 through OATP6. Humans contain 12 OATPs encoded by 11 solute carrier of organic anion transporting polypeptide (SLCO) genes: OATP1A2, OATP1B1, OATP1B3, the splice variant OATP1B3-1B7, OATP1C1, OATP2A1, OATP2B1, OATP3A1, OATP4A1, OATP4C1, OATP5A1, and OATP6A1. Most of these proteins are expressed in epithelial cells, where they mediate the uptake of structurally unrelated organic anions, cations, and even neutral compounds into the cytoplasm. The best-characterized members are OATP1B1 and OATP1B3, which have an important role in drug metabolism by mediating drug uptake into the liver and are involved in drug-drug interactions. In this review, we aimed to (1) provide a historical perspective on the identification of OATPs and their nomenclature and discuss their phylogenic relationships and molecular characteristics; (2) review the current knowledge of the broad substrate specificity and their role in drug disposition and drug-drug interactions, with a special emphasis on human hepatic OATPs; (3) summarize the different experimental systems that are used to study the function of OATPs and discuss their advantages and disadvantages; (4) review the available experimental 3-dimensional structures and examine how they can help elucidate the transport mechanisms of OATPs; and (5) finally, summarize the current knowledge of the regulation of OATP expression, discuss clinically important single-nucleotide polymorphisms, and outline challenges of physiologically based pharmacokinetic modeling and in vitro to in vivo extrapolation. SIGNIFICANCE STATEMENT: Organic anion transporting polypeptides (OATPs) are a family of 12 uptake transporters in the solute carrier superfamily. Several members, particularly the liver-expressed OATP1B1 and OATP1B3, are important drug transporters. They mediate the uptake of several endobiotics and xenobiotics, including statins and numerous other drugs, into hepatocytes, and their inhibition by other drugs or reduced expression due to single-nucleotide polymorphisms can lead to adverse drug effects. Their recently solved 3-dimensional structures should help to elucidate their transport mechanisms and broad substrate specificities.

Polypharmacological approaches have significant potential for the treatment of various complex diseases, including infectious bacteria-related diseases. Actually, multitargeting agents can achieve better therapeutic effects and overcome the drawbacks of monotherapy. Although multidrug multitarget strategies have demonstrated the ability to inactivate infectious bacteria, several challenges have been pointed out. In this way, multitarget direct ligands approaches appear to be a rational and sustainable strategy to combat antibiotic resistance. By combining different pharmacophores, antibiotic hybrids stand out as a promising application in the field of bacterial infections. These new chemical entities can achieve synergistic interactions that allow to extend the spectrum of action and target multiple pathways. In addition, antibiotic hybrids can reduce the likelihood of resistance development and provide improved chemical stability. It is worth highlighting that despite the efforts of the scientific community to discover new solutions for the most complex diseases, there is a significant lack of studies on biofilm-associated infections. This review describes the different polypharmacological approaches that can be used to treat bacterial infections with a particular focus, whenever possible, on those promoted by biofilms. By exploring these innovative approaches, we aim to inspire further research and progress in the search for effective treatments for infectious bacteria-related diseases, including biofilm-related ones. SIGNIFICANCE STATEMENT: The importance of the proposed topic lies in the escalating challenge of antibiotic resistance, particularly in the context of infectious bacteria-related infections. Polypharmacological approaches, such as antibiotic hybrids, represent innovative strategies to combat bacterial infections. By targeting multiple signaling pathways, these approaches not only enhance therapeutic effect but also reduce the development of resistance while improving the drug's chemical stability. Despite the urgent need to combat bacterial infectious diseases, there is a notable research gap, in particular in biofilm-related ones. This review highlights the critical importance of exploring polypharmacological approaches with the aim of motivating further research and advances in effective treatments for infectious bacteria, including biofilm related infections.

Relapse to drug use is often preceded by drug craving. Clinical observations in the 1980s led clinical investigators to postulate that cue-induced cocaine craving may increase during abstinence. Over 2 decades ago, investigators identified an analogous phenomenon in rats of time-dependent increases in drug-seeking behavior during homecage abstinence and termed it incubation of cocaine craving. In 2011, we reviewed the first decade of studies on brain mechanisms of incubation of drug craving. In this review, we provide an update on incubation-related brain mechanisms from studies published since 2011. We first review studies using the standard method of incubation after homecage-forced abstinence from cocaine, methamphetamine, opioid drugs, and nicotine. Next, we review studies using newer methods to study incubation after voluntary abstinence in the drug environment. In these studies, abstinence is achieved by either providing rats alternative nondrug rewards in a choice setting or introducing rats to adverse consequences to drug seeking or taking. We then discuss translational human studies on incubation of cue-induced drug craving. We conclude by discussing several emerging topics, including sex differences in incubation of drug craving, role of sleep patterns, and similarities and differences in mechanisms of incubation of craving across drug classes and abstinence conditions. Our 2 main conclusions are as follows: (1) across drug classes, there are both similarities and differences in mechanisms of incubation of drug craving after forced abstinence, and (2) the method used to achieve abstinence (forced or voluntary) can influence the mechanisms controlling incubation of drug craving or its expression. SIGNIFICANCE STATEMENT: This article reviews results from preclinical and clinical studies published since 2011 on neurobiological mechanisms of incubation of drug craving after homecage-forced abstinence or voluntary abstinence in the drug environment. This article also reviews translational human studies on incubation of cue-induced subjective drug craving and brain response during abstinence. The results of the studies reviewed indicate that multiple brain mechanisms control incubation of drug craving after homecage-forced abstinence or voluntary abstinence.