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Phytochemistry of Harmal
Published in Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen, Harmal, 2017
Ephraim Shmaya Lansky, Shifra Lansky, Helena Maaria Paavilainen
Synthetic derivatives of harmine are as much as four times more cytotoxic as harmine against HGC-27 human gastric carcinoma and HT-29 human colon cancer cells (Shankaraiah et al. 2016). Harmine is one of very few natural compounds known to inhibit breast cancer resistance protein (BCRP), a key mediator of breast cancer resistance to chemotherapeutic drugs (Ma and Wink 2010), and similarly, newly synthesized harmine analogues at the University of Bonn, Germany, have been shown to be as potent as another known inhibitor of BCRP, the mycotoxin fumitremorgin C (FTC), Ko143, isolated from the fungus Aspergillus fumigatus (Spindler et al. 2016) (Figure 6.15), newly synthesized harmine analog at China’s Shihezi University, in cooperation with the Xinjiang Huashidan Drug-Discovery Co., Ltd., Urumchi, was shown to have strong antiproliferative activity in human lung, stomach, ovary, and prostate cancer cell lines through multiple anti-angiogenic mechanisms related to vascular epithelial growth factor (VEGF) activity and its receptor (VEGFR) (Ma et al. 2016). Another synthetic harmine derivative proved effective against B cell lymphoma through caspase activation (Gao et al. 2014). A different group at University of Namur, Belgium, created an analog of harmine with augmented potency and complexed it with maltodextrin to achieve superior drug solubility (Meinguet et al. 2015a) in a portfolio of harmine analogs for antiproliferative purposes in experimental oncology (Meinguet et al. 2015b). Harmine was the reference compound for all of the aforementioned studies (Bruel et al. 2014).
Resistance Mechanisms of Tumor Cells
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Multidrug resistance is a major problem for many therapeutic interventions, because the expression of distinct multidrug transporter proteins (ATP-driven ABC transporters) is a natural defense mechanism of our cells and, obviously, also part of the detoxifying capacity of cancer cells. Several ABC transporter families are known to confer this ability. However, clinically most relevant were only very few, which are ABCB1 (MDR1, PGP), ABCC1 (MRP1), and ABCG2 (MXR, ABCP). They represent enzymes that lower the adverse effects of poisons by simply pumping them in an ATP-dependent manner to the outside (efflux transporters). They are ubiquitously expressed, but certain organs or tissues have additional ABC transporters for protection. MDR1 was the first efflux transporter ever described because of its ability to confer drug resistance to cancer cells (Roninson et al., 1986). It is preferentially pumping uncharged or positively charged hydro-phobic compounds, while MRP1 pumps organic anions including drug-conjugates (glutahione, glucuronate, or sulfate). MXR pumps several drugs like, e.g., topoisomerase inhibitors, anthracyclines, camptothecin, TKI, antimetabolites mitoxanthrones, anthracyclines, topothecan, flavopiridol, and methotrexate. Noteworthy, most ABC transporters can be inactivated by a distinct set of drugs. Drugs known to inhibit MDR1 (Amiodaron, Azithromycin, Captopril, Chinidin, Chinin, Clarithromycin, Ciclosporin, Elacridar, Piperin, Quercetin, Reserpin, Ritonavir, Tariquidar, and Verapamil) can be used to manipulate tumor cells to make them more sensitive against chemotherapy. Similarly, nucleoside reverse transcriptase inhibitors (NRTIs: Zidovudin, Stavudin, Lamivudin, Didanosin, Abacavir) or non-nucleoside reverse transcriptase inhibitors (NNRTIs: Nevirapin, Efavirenz, and Delavirdin)—usually used for HIV treatment—have the capability to inhibit MRP1 in a dose-dependent fashion (Weiss et al., 2007). MRP1 is also very important for the maintenance of the blood–brain barrier and thus counteracts brain tumor treatment. In those cases, both Reversan (inhibitor of MDR1 and MRP1; Burkhardt et al., 2009) and MK571 (inhibitor of MRP1 and MRP4; Gekeler et al., 1995) can be used to enhance treatment efficacy (Tivnan et al., 2015). The fungal toxin Fumitremorgin C (Rabindran et al., 2000) and Curcumin (Zhou et al., 2015) act both as inhibitors of ABCG2 and breast cancer resistance protein (BCRP: mediates resistance to mitoxantrone and doxorubicin); however, clinical studies are yet missing to use this compound alone or in combination with the above-mentioned chemotherapeutic drugs for the treatment of patients (Hasanabady and Kalalina, 2016).
Study on mechanism of low bioavailability of black tea theaflavins by using Caco-2 cell monolayer
Published in Drug Delivery, 2021
Fengfeng Qu, Zeyi Ai, Shuyuan Liu, Haojie Zhang, Yuqiong Chen, Yaomin Wang, Dejiang Ni
TF, TF3G, TF3’G, and TFDG were purchased from Shanghai Yuanye Biological Technology Company Limited (Shanghai, China). Caco-2 cells were purchased from cell bank of Chinese Academy of Science, Shanghai. Dulbecco modified eagle medium (DEME), fetal bovine serum, Hank’s balanced salts solution (HBSS) and other cell culture medium components were all purchased from Hyclone (LA, USA). Verapamil (Vep) and MK-571 were obtained from Sigma-Aldrich (DA, Germany). Cyclosporin A (CsA) was obtained from Cayman Chemical (MI, USA). Fumitremorgin C (FTC) was obtained from MedcChemExpress (NJ, USA). The primary antibodies of multidrug resistance asscioated proteins (MRP1, 14685S; MRP2, 12559S; MRP3, 14182S), P-glycoprotein (P-gp, 13342S), and breast cancer resistance protein (BCRP, 42078S) were purchased from Cell Signaling Technology (MA, USA). Horseradish peroxidase (HRP)-conjugated goat anti-rabbit (SA00001-2) was purchased from Proteintech (Wuhan, China). Radio immunoprecipitation assay (RIPA) lysis buffer and phenylmethanesulfonyl fluoride (PMSF) were purchased from Beyotime (Shanghai, China). Poly-vinylidene fluoride (PVDF) membranes, enhanced chemiluminescence reagents (ECL) and other western reagents were obtained from Service Biological Technology Co., Ltd (Wuhan, China). BCA protein assay kit and cell counting kit-8 (CCK-8) were purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China). Cell RNA extraction kit, cDNA synthesis kit and SYBR Green qPCR Mix were purchased from Aidlab (Beijing, China). All the primers were synthesized by Sangon Biotech (Shanghai, China).
Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Mohammad Feyzizadeh, Ashkan Barfar, Zeinab Nouri, Muhammad Sarfraz, Parvin Zakeri-Milani, Hadi Valizadeh
ABCG2 inhibitors are classified into selective ABCG2 modulator, wide-spectrum MDR suppressors, and tyrosine kinase inhibitors (TKIs) [55]. Fumitremorgin C is a specific ABCG2 inhibitor that could resensitize colon carcinoma to mitoxantrone [56]. As previously mentioned, tariquidar and elacridar are broad-spectrum ABCG2 inhibitors that could antagonize P-gp in addition to their ABCG2 inhibitory effects. Accumulating evidence has demonstrated that TKIs overcome MDR via inhibiting the activity of ABC transporters [57]. At high concentrations, Erlotinib and lapatinib, which belong to TKIs, directly repressed the drug outflow activity of ABCG2 [58,59].
Preclinical absorption, distribution, metabolism, excretion and pharmacokinetics of a novel selective inhibitor of breast cancer resistance protein (BCRP)
Published in Xenobiotica, 2018
Mingxiang Liao, Bei-Ching Chuang, Qing Zhu, Yuexian Li, Emily Guan, Shaoxia Yu, Johnny Yang, Shimoga Prakash, Cindy Q. Xia
In recent years, efforts have been made to select or synthesize more potent and specific BCRP inhibitors through high-throughput screening of chemical compound libraries or synthesis of new classes of compounds (Li et al., 2016; Marighetti et al., 2015; Pires Ado et al., 2016; Song et al., 2017; Wiese, 2015). However, the available PK and pharmacological data of those BCRP inhibitors are insufficient, which limits their application to in vitro, in vivo and clinical studies. Based on the potency and specificity, the commonly used BCRP inhibitors can be categorized as those with relatively high potency and high specificity, such as fumitremorgin C and its analog Ko143, high potency and low specificity, including elacridar and tariquidar which are also P-gp inhibitors, and others, such as cyclosporine A (Allen et al., 2002; Gardner et al., 2009; Kruijtzer et al., 2002; Xia et al., 2007a). Ko143 (Figure 1A) is less toxic than fumitremorgin C, and has been widely used for in vitro ADME studies (Allen et al., 2002; Lee et al. 2015; Muenster et al., 2008; Xia et al. 2007b). However, high plasma clearance and low bioavailability impeded the application of Ko143 on BCRP studies in rats, a standard preclinical PK model (Li et al., 2016; Weidner et al. 2015). A recently described BCRP inhibitor (ML753286, known as Compound A in Li et al., 2016; Figure 1B), is a Ko143 analog showing an improved PK profile in rats, and is being considered as a promising selective BCRP inhibitor in animal models (Li et al., 2016). In the present work, a thorough characterization of preclinical in vitro and in vivo ADME properties of ML753286 was performed in order to support the application of this novel BCRP inhibitor on the in vivo evaluation of efflux transporter effects on PK profiles to optimize drug design and screening.