China
Africa
Explore chapters and articles related to this topic
BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
Other mechanisms of resistance to PARP inhibitors have been reported. In a genetically engineered mouse model of BRCA1-associated breast cancer exposed to AZ2281, resistance developed secondary to upregulation of the Abcb1a/b gene, encoding the P-glycoprotein efflux pump. With the coadministration of tariquidar, a P-glycoprotein inhibitor, resistance was reversed [96]. In addition, the 53BP1 protein could play a role in resistance to PARP inhibition, based on its regulation of DNA repair in BRCA-deficient cells. In a cell with normal BRCA1 function, after a DSB, BRCA1 displaces 53BP1, and HR repair is completed. In the case of BRCA1 mutation and absence of 53BP1, downstream proteins of HR are still initiated and HR is still activated. It is only when BRCA1 is mutated and 53BP1 is present that 53BP1 binds to the site of the DSB preventing HR, but allowing for error prone NHEJ to direct repair. In BRCA-deficient mice bearing mammary tumors, loss of 53BP1 reduces tumorigenesis.
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
Strategies aimed at overcoming MDR have long involved nanoparticle encapsulation of chemotherapeutics and an MDR modulator. As examples, Lee and coworkers [83] have formulated targeted liposomes with doxorubicin and verapamil, a P-glycoprotein inhibitor, and Wu and coworkers [84] have developed hybrid nanoparticles comprising lipids and polymers coloaded with doxorubicin and GG918, a BCRP inhibitor. Compared with free-drug controls and chemotherapeutic nanoparticles without MDR inhibitors, the doxorubicin/ verapamil and doxorubicin/GG918 formulations were more cytotoxic to leukemia and MDR breast cancer cell lines, respectively. Studies have also examined combinations of drugs, such as paclitaxel with P-glycoprotein inhibitors, like tariquidar [85]. Recently, RNAi strategies to inhibit efflux pumps, such as P-glycoprotein, have also been explored. As an example, Lavasanifar and coworkers [86] developed a multifunctional polymer micelle system comprising poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) encapsulating doxorubicin and a short interfering RNA (siRNA) targeting MDR-1 for gene silencing of P-glycoprotein expression.
Oxime Research
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Significant progress has been achieved in crossing the BBB with the help of targeted nanoparticle drug delivery. Some reactivators (HI-6 and obidoxime) bound to biodegradable human serum albumin nanoparticles were able to cross an in vitro BBB model (Wagner et al., 2010). Safe and effective modulation of transport across the BBB also represents an attractive approach for targeting drugs into the brain. Inhibition of the active efflux transporter P-glycoprotein located in the endothelial cell membrane was shown to improve the BBB permeability. For example, the administration of tariquidar, a specific potent noncompetitive P-glycoprotein pump inhibitor, resulted in a twofold increase in HI-6 levels in the brain during the first hour after i.m. administration, whereas the plasma HI-6 level was not affected (Joosen et al., 2011). Thus, the potential use of inhibitors of efflux transport is an alternative approach to increasing the CNS delivery of available reactivators, for which highly polar characteristics are considered to be a key structural requirement. In addition, adenosine receptor signaling was shown to modulate the BBB permeability in vivo, facilitating the entry for dextrans and antibodies (Carman et al., 2011). Thus, adenosine receptor signaling may be a promising strategy for improvement in the BBB permeability for therapeutically important oximes.
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
As a third-generation P-gp inhibitor, tariquidar is not selective in action for P-gp since it possesses the ability to attach to ABCG2 transporter, too [46]. Tariquidar could restore the sensitivity of NCI/ADRRes cells to doxorubicin (0–100 μM) by potent suppression of P-gp. The NCI/ADRRes cells exhibited a 104-fold resistance to doxorubicin in the absence of tariquidar (IC50 = 15.7 ± 4.8 μM). However, tariquidar (300 nM) enhanced the potency of doxorubicin and diminished the resistance to doxorubicin (sevenfold). The high level of resistance to vinblastine (2333-fold) at the dose of 0–100 μM was decreased to about sevenfold in the presence of tariquidar (300 nM) [47]. The toxicity of tariquidar in phase III clinical trials and susceptibility to hydrolysis limited its applicability [48]. Therefore, to optimize the pharmacological properties of tariquidar, several analogs of this compound have been synthesized. UR-MB108 and UR-MB136 are two derivatives of tariquidar that displayed a strong potency with the IC50 value around 80 nM. Their inhibitory effects on ABCG2 were related to suppressing ATPase activity [49]. It has been shown that elacridar, a dual ABCB1 and ABCG2 modulator, given in combination with lapatinib, affected the pharmacokinetics of lapatinib and increased the diffusion of lapatinib inside the cerebrospinal fluid and brain; however, no change in Cmax of lapatinib in blood plasma was observed [50]. Interestingly, zosuquidar, a third-generation P-gp inhibitor, augmented oral etoposide absorption, diminished etoposide clearance, and thereby augmented the intestinal absorption of etoposide [51].
An updated patent review on P-glycoprotein inhibitors (2011-2018)
Published in Expert Opinion on Therapeutic Patents, 2019
Marcello Leopoldo, Patrizia Nardulli, Marialessandra Contino, Francesco Leonetti, Gert Luurtsema, Nicola Antonio Colabufo
On the other hand, tariquidar (Figure 1(a)) in several cells seems to be ambiguously active because it is both P-gp inhibitor and in the meantime substrate toward other pumps, such as, the Breast Cancer Resistance Protein (BCRP). BCRP has an half transporter overlapping P-gp structure and practically acts as a dimer [9,10]. Therefore, tariquidar activity is due to the balance of these two pumps present at tumor cell membranes and will be possible observe a potent or a weak activity of this ligand in the studied model based on the different quantitative presence of P-gp and BCRP.
1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design
Published in Expert Opinion on Drug Discovery, 2021
Banoth Karan Kumar, Kondapalli Venkata Gowri Chandra Sekhar, Subhash Chander, Selvaraj Kunjiappan, Sankaranarayanan Murugesan
THIQ is a versatile scaffold that is present in numerous drug molecules and has also been reported to possess a plethora of pharmacological properties. The simple synthetic route to generate the core scaffold combined with the nucleophilicity of the secondary nitrogen makes it easier to hybridize with other versatile scaffolds of interest, making THIQ a vital scaffold for drug design. However, the anticancer potential of THIQ analogs continues to be an enigma. The information amassed in this review aims to shed light on the anticancer potential of THIQ analogs. THIQs possess enormous potential as anticancer agents. These analogs exhibit their anticancer property by inhibiting epigenetic enzymes like PRMT5 and HDACs, anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, receptors such as ER and AR as well as key targets of estrogen metabolism- aromatase and STS. Apart from being anticancer agents themselves, they have also been demonstrated to aid existing anticancer drugs by reversing their resistance via inhibiting the functions of MDR transporter P-gp. Several P-gp inhibitors such as tariquidar and elacridar have been evaluated clinically, demonstrating the ability of THIQs to act as combination therapy with existing drugs. The most promising THIQ analogs for each target described in this review are summarized in Table 1. Privileged scaffolds, as coined by Evans et al., denote molecular fragments that can bind to multiple receptors with high affinity [144,145]. THIQs have been reported to bind to multiple targets to exhibit their pharmacological properties [146]. As described in the present review, THIQs also possess a high affinity toward multiple cancer targets with good in vitro or in vivo anticancer activity. Hence, THIQs can be regarded as a ‘privileged scaffold’ and will continue to be a ‘vital scaffold’ in the field of medicinal chemistry for the development of potent and safe novel anticancer agents.