The Repurposing of Non-Peptide Neurokinin-1 Receptor Antagonists as Antitumor Drugs: An Urgent Challenge for Aprepitant.

The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration, angiogenesis, the Warburg effect, and the prevention of apoptosis. Tumor cells overexpress NK-1R, which influences their viability. A typical specific anticancer strategy using NK-1R antagonists, irrespective of the tumor type, is possible because these antagonists block all the effects mentioned above mediated by SP on cancer cells. This review will update the information regarding using NK-1R antagonists, particularly Aprepitant, as an anticancer drug. Aprepitant shows a broad-spectrum anticancer effect against many tumor types. Aprepitant alone or in combination therapy with radiotherapy or chemotherapy could reduce the sequelae and increase the cure rate and quality of life of patients with cancer. Current data open the door to new cancer research aimed at antitumor therapeutic strategies using Aprepitant. To achieve this goal, reprofiling the antiemetic Aprepitant as an anticancer drug is urgently needed.

Peptidergic Systems as Antitumor Targets: A Right Direction to Fight Cancer?

Undoubtedly, much progress has been made in treating cancer over the past few years, but unfortunately, 28 [...].

Involvement of the Opioid Peptide Family in Cancer Progression.

Peptides mediate cancer progression favoring the mitogenesis, migration, and invasion of tumor cells, promoting metastasis and anti-apoptotic mechanisms, and facilitating angiogenesis/lymphangiogenesis. Tumor cells overexpress peptide receptors, crucial targets for developing specific treatments against cancer cells using peptide receptor antagonists and promoting apoptosis in tumor cells. Opioids exert an antitumoral effect, whereas others promote tumor growth and metastasis. This review updates the findings regarding the involvement of opioid peptides (enkephalins, endorphins, and dynorphins) in cancer development. Anticancer therapeutic strategies targeting the opioid peptidergic system and the main research lines to be developed regarding the topic reviewed are suggested. There is much to investigate about opioid peptides and cancer: basic information is scarce, incomplete, or absent in many tumors. This knowledge is crucial since promising anticancer strategies could be developed alone or in combination therapies with chemotherapy/radiotherapy.

Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies.

Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system's high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.

Neurotensin and Alcohol Use Disorders: Towards a Pharmacological Treatment.

Harmful alcohol use is responsible for a group of disorders collectively named alcohol use disorders (AUDs), according to the DSM-5 classification. The damage induced by alcohol depends on the amount, time, and consumption patterns (continuous and heavy episodic drinking). It affects individual global well-being and social and familial environments with variable impact. Alcohol addiction manifests with different degrees of organ and mental health detriment for the individual, exhibiting two main traits: compulsive drinking and negative emotional states occurring at withdrawal, frequently causing relapse episodes. Numerous individual and living conditions, including the concomitant use of other psychoactive substances, lie in the complexity of AUD. Ethanol and its metabolites directly impact the tissues and may cause local damage or alter the homeostasis of brain neurotransmission, immunity scaffolding, or cell repair biochemical pathways. Brain modulator and neurotransmitter-assembled neurocircuitries govern reward, reinforcement, social interaction, and consumption of alcohol behaviors in an intertwined manner. Experimental evidence supports the participation of neurotensin (NT) in preclinical models of alcohol addiction. For example, NT neurons in the central nucleus of the amygdala projecting to the parabrachial nucleus strengthen alcohol consumption and preference. In addition, the levels of NT in the frontal cortex were found to be lower in rats bred to prefer alcohol to water in a free alcohol-water choice compared to wild-type animals. NT receptors 1 and 2 seem to be involved in alcohol consumption and alcohol effects in several models of knockout mice. This review aims to present an updated picture of the role of NT systems in alcohol addiction and the possible use of nonpeptide ligands modulating the activity of the NT system, applied to experimental animal models of harmful drinking behavior mimicking alcohol addiction leading to health ruin in humans.

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families.

The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, and CGRP receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis. Several antitumor therapeutic strategies, including peptide receptor antagonists, are discussed. The main research lines to be developed in the future are mentioned.

Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers.

The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol's nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol's effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol's action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.

Targeting NPY, CRF/UCNs and NPS Neuropeptide Systems to Treat Alcohol Use Disorder (AUD).

BACKGROUND: The term Alcohol Use Disorder (AUD) incorporates different states of disease related to the recurrent use of alcohol and linked to the relevant impairment, disability and failure to perform major responsibilities in different realms. Many neurotransmitter systems are involved in the phases or states of alcoholism from reward mechanisms, associated to binge intoxication, to stress and anxiety linked to relapse and withdrawal. Some neuropeptides play a key function in the control of anxiety and stress, and establish a close relationship with the pathological mechanisms underlying alcohol addiction. Among them, Neuropeptide Y (NPY), Corticotropin-releasing factor (CRF)/Urocortins and Neuropeptide S (NPS) cross-talk, and are responsible for some of the maladaptation processes that the brain exhibits during the progression of the disease. METHOD: In this study, we review the literature mainly focused on the participation of these neuropeptides in the pathophysiology of AUD, as well as on the use of antagonists designed to investigate signaling mechanisms initiated after ligand binding and their connection to biochemical adaptation events coupled to alcohol addiction. The possibility that these systems may serve as therapeutic objectives to mitigate or eliminate the harm that drinking ethanol generates, is also discussed. CONCLUSION: The peptide systems reviewed here, together with other neurotransmitter systems and their mutual relationships, are firm candidates to be targeted to treat AUD.

Morphology of retinal vessels in the optic disk in a Göttingen minipig experimental glaucoma model.

OBJECTIVE: To compare the morphology of normal, healthy Gottingen minipig retinal vessels of the optic disk with experimentally induced glaucomatous optic disks in order to identify the glaucomatous excavation. Present results were compared to human glaucoma findings. PROCEDURE: Sixteen eyes from eight Göttingen minipigs were studied using fundoscopic photography and fluorescein angiography. Experimental glaucoma was then induced in the left eyes over 14 months, and changes in the optic disk vessels were assessed using fundoscopic photography and fluorescein angiography. The changes were compared with those previously reported in humans. RESULTS: Regarding the number of vessels, the location from where they emerge and the sectors of the optic disk that they cross, arterial and retinal vessels in Göttingen minipigs present a more asymmetric layout than in humans. The central excavation is filled by the central venous ring. Changes in the glaucomatous optic disk include arteriolar incurvation, and sometimes, nasal, and peripheral displacement of the arterioles that emerge between the ganglion cell axons of the neuroretinal ring. No angiographic changes were observed in the experimental glaucoma model. CONCLUSIONS: The changes in the glaucomatous optic disk of the minipig imply a predominant involvement of the arterioles. However, in humans with primary open-angle glaucoma (POAG), both the arterioles and the venules are displaced, and the central excavation is easier to distinguish, because of the absence of a central venous ring.