Herb X reverses multi-drug resistance by increasing drug permeability in blood–brain barrier and intestinal barrier

Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

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ABCB subfamily (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f152/2019.4 ◽

2019 ◽

Vol 2019 (4) ◽

Author(s):

Mary Vore

Keyword(s):

Drug Resistance ◽

Tumor Cells ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Multi Drug Resistance ◽

Drug Resistant ◽

Blood Brain

The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance [4].

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Faculty Opinions recommendation of Microfluidic blood-brain barrier model provides in vivo-like barrier properties for drug permeability screening.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726494757.793534155 ◽

2017 ◽

Author(s):

Marco Soriani

Keyword(s):

Blood Brain Barrier ◽

Barrier Properties ◽

Brain Barrier ◽

Drug Permeability ◽

Blood Brain ◽

Blood Brain Barrier Model ◽

Barrier Model

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Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

Journal of Translational Medicine ◽

10.1186/s12967-021-02995-z ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xiuli Lin ◽

Yingying Liu ◽

Lili Ma ◽

Xiaomeng Ma ◽

Liping Shen ◽

...

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Gut Microbiota ◽

Blood Brain Barrier ◽

Intestinal Barrier ◽

Brain Barrier ◽

Autoimmune Encephalomyelitis ◽

Gm Csf ◽

Blood Brain ◽

Gut Microbiota Dysbiosis ◽

Experimental Autoimmune

Abstract Background Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methods Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood–brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. Results Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood–brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. Conclusions Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

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Hurdles with Using In Vitro Models to Predict Human Blood-brain Barrier Drug Permeability: A Special Focus on Transporters and Metabolizing Enzymes

Current Drug Metabolism ◽

10.2174/1389200211309010120 ◽

2012 ◽

Vol 14 (1) ◽

pp. 120-136 ◽

Cited By ~ 1

Author(s):

Ramzi Shawahna ◽

Xavier Decleves ◽

Jean-Michel Scherrmann

Keyword(s):

Blood Brain Barrier ◽

Human Blood ◽

In Vitro Models ◽

Brain Barrier ◽

Special Focus ◽

Metabolizing Enzymes ◽

Drug Permeability ◽

Blood Brain

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Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Pharmaceutics ◽

10.3390/pharmaceutics12121134 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1134

Author(s):

Manuela Gernert ◽

Malte Feja

Keyword(s):

Drug Delivery ◽

Drug Resistance ◽

Adverse Effects ◽

Blood Brain Barrier ◽

Neurological Diseases ◽

Invasive Procedure ◽

Resistance Mechanisms ◽

Brain Barrier ◽

Blood Brain ◽

Drug Concentrations

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

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