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Embelia ribes (False Black Pepper) and Gymnema sylvestre (Sugar Destroyer)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Chandrabose Selvaraj, Chandrabose Yogeswari, Sanjeev Kumar Singh
G. sylvestre ethanolic extract has potent activity against human skin melanoma and skin papilloma models, but has no toxic effect on normal liver cell lines (Chakraborty et al., 2013). It also has a significant inhibitory effect on breast cancer resistant protein (BCRP). The administration of flavonoids from G. sylvestre effectively suppresses BCRP expression, which improves the activity of BCRP substrates methotrexate, topotecan, epirubicin, and daunorubicin, resulting in increased systemic absorption. Several studies have revealed G. sylvestre hypolipidemic activity. The administration of a G. sylvestre leaf extract to Wister female rats significantly reduced cholesterol, low-density lipoprotein, and triglyceride levels while increasing HDL levels (Singh et al., 2017). G. sylvestre hydroalcoholic leaf extract also significantly lowers LDL. The study was conducted with supplements of a higher level of cholesterol, LDL, triglyceride, and effectively lowering the level of HDL for seven days, after which the mice were treated with G. sylvestre leaf extract, which results in lowering the level of triglycerides, LDL, and cholesterol and also increasing the level of HDL due to the presence of chemical constituents such as saponins, tannins, and flavonoids (Rachh et al., 2010; Dholi and Raparla, 2014). Similar results were reported in several studies with diabetic rats (Bishayee and Chatterjee, 1994; Kumar et al., 2013).
Principles of Nanoparticle Design for Overcoming Biological Barriers to Drug Delivery *
Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Elvin Blanco, Haifa Shen, Mauro Ferrari
Although drug resistance can indeed be multifactorial, arising from combined mechanisms, such as activation of detoxifying systems and defective apoptotic pathways, classic MDR is effected through the efflux action of ATP-dependent transporters that are members of a superfamily of proteins that possess an ATP-binding cassette (ABC) [78]. MDR in cancer frequently arises from the overexpressed ABC transporter, P-glycoprotein, an efflux pump capable of binding several distinct hydrophobic chemotherapeutics [79]. Although it is found overexpressed in cancer and arises from cellular adaptations to stress, such as hypoxia, P-glycoprotein is normally found in organs, such as the brain, testis, placenta, liver, gastrointestinal tract and kidneys, tasked with protecting these organs from toxins [80]. Further insights into MDR in cells not expressing P-glycoprotein led to the discovery of MDR-associated protein-1 and the breast cancer resistance protein (BCRP) [81]. Consequently, research efforts have been devoted to the investigation of efflux pump inhibitors, with verapamil (Covera) and cyclosporine A emerging as first-generation antagonists [82].
Lung transporters and absorption mechanisms in the lungs
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Mohammed Ali Selo, Hassan H.A. Al-Alak, Carsten Ehrhardt
Approximately 50 genes that are divided into eight subfamilies are encoding ABC transporters in humans (34,35). Among these, P-glycoprotein (P-gp), multidrug resistance-related protein 1–8 (MRP1–8), and breast cancer resistance protein (BCRP) are expressed in lung tissues at varying levels and are well known for their role in multidrug resistance (MDR).
Regulation of BCRP expression and sulfasalazine pharmacokinetics by the nuclear receptor REV-ERBα
Published in Xenobiotica, 2023
Chunhong Wu, Yifei Xiao, Caimei Wu, Dihao Xie, Meixue Luo, Dingyi Yao, Min Chen, Danyi Lu
Breast cancer resistance protein (BCRP, also known as ABCG2) belongs to membrane efflux transporters of the ATP-binding cassette (ABC) superfamily. It is highly expressed in barrier tissues such as the liver, small intestine, kidney, and brain, and plays an important role in the transport of a wide range of endogenous and exogenous substances including drugs (e.g. sulfasalazine, topotecan, and methotrexate) (Meyer zu Schwabedissen and Kroemer 2011; Jani et al. 2014; Mao and Unadkat 2015). Since BCRP is localised on the luminal membrane of enterocytes and on the canalicular membrane of hepatocytes, it restricts intestinal absorption and facilitates the hepatobiliary excretion of substrate drugs (Maliepaard et al. 2001). Due to the critical roles of BCRP in drug pharmacokinetics and pharmacodynamics, identification of a new regulator of BCRP expression and understanding the regulatory mechanism thereof may have potential significance for precise drug therapy. To date, several transcription factors (e.g. HIF1, NRF2, and PPARγ) have been reported to regulate BCRP transcription and expression by interacting with specific cis-acting elements located in the proximal promoter region of the BCRP gene (Nakanishi and Ross 2012; Zattoni et al. 2022). In addition, the expression of BCRP is controlled at epigenetic and posttranslational levels (Chen et al. 2019). However, it is still unknown whether and how REV-ERBα regulates BCRP expression and activity.
An evaluation of sotorasib for the treatment of patients with non–small cell lung cancer with KRASG12C mutations
Published in Expert Opinion on Pharmacotherapy, 2022
Garth W. Strohbehn, Kamya Sankar, Angel Qin, Gregory P. Kalemkerian
Based on the findings of CodeBreaK 100, the FDA granted sotorasib accelerated approval for the 2L+ treatment of metastatic KRASG12C-mutant NSCLC [19], with full regulatory approval pending the submission of additional clinical trial results, three additional post-marketing requirements, and one post-marketing commitment [41]. First, full regulatory approval will depend upon the demonstration of 2L+ PFS benefit of sotorasib against a standard-of-care treatment (docetaxel) in the CodeBreaK 200 randomized trial [35]. As noted above, preliminary data from this study have been presented, but have not yet been published. Second, the FDA has required a prospective, multicenter, randomized trial to further characterize the safety and efficacy of sotorasib 960 mg daily versus a ‘lower daily dose’ [41]. Third, the FDA has required a prospective study aimed at identifying a safe and appropriate sotorasib dose for patients with moderate and severe hepatic impairment. Fourth, a sponsored clinical study must assess the interaction between sotorasib and substrates of breast cancer resistance protein (BCRP) to fully characterize transporter-mediated drug interactions. Finally, the manufacturer has agreed to file a report detailing the safety and efficacy of sotorasib in African-American patients with KRASG12C-mutant NSCLC.
Sorafenib for hepatocellular carcinoma: potential molecular targets and resistance mechanisms
Published in Journal of Chemotherapy, 2022
Organic cation transporter-1 (OCT1) plays the most important role in sorafenib uptake. OCT1 at the plasma membrane is related to superior results in sorafenib-treated patients [14]. Drug uptake reduction can lead to resistance. SLC22A1 down-regulation encoding solute carrier OCT1 has been found unable to transport sorafenib. The two SLC22A1 variants, R61S fs*10 and C88A fs*16 abolished OCT1-mediated uptake of substrate tetraethylammonium and leads to a reduction in sorafenib sensitivity [15]. The higher expression of breast cancer resistance protein has been found in HCC and responsible for sorafenib efflux. Increased activity of HER3 (human epidermal growth factor receptor 3) pathways reduced the sensitivity to sorafenib, and high levels of p-MET (phosphorylated mesenchymal epithelial transition) reduced clinical response [16].