Hernandezine, a Bisbenzylisoquinoline Alkaloid with Selective Inhibitory Activity against Multidrug-Resistance-Linked ATP-Binding Cassette Drug Transporter ABCB1

Abstract

The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein, MDR1) is the most studied mechanism of multidrug resistance (MDR), which remains a major obstacle in clinical cancer chemotherapy. Consequently, resensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 has been considered as a potential strategy to overcome ABCB1-mediated MDR in cancer patients. However, the task of developing a suitable modulator of ABCB1 has been hindered mostly by the lack of selectivity and high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively nontoxic nature of natural products, developing a potential modulator of ABCB1 from natural sources is particularly valuable. Through screening of a large collection of purified bioactive natural products, hernandezine was identified as a potent and selective reversing agent for ABCB1-mediated MDR in cancer cells. Experimental data demonstrated that the bisbenzylisoquinoline alkaloid hernandezine is selective for ABCB1, effectively inhibits the transport function of ABCB1, and enhances drug-induced apoptosis in cancer cells. More importantly, hernandezine significantly resensitizes ABCB1-overexpressing cancer cells to multiple chemotherapeutic drugs at nontoxic, nanomolar concentrations. Collectively, these findings reveal that hernandezine has great potential to be further developed into a novel reversal agent for combination therapy in MDR cancer patients.

Biologically active isoquinoline alkaloids covering 2014–2018

“…42 (R)-(+)-1-Benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (42) from P. oleracea showed anti-inflammatory and β2-adrenergic receptor agonist activities. 27 Laudanosine (43), pseudolaudanine (44), and rugosinone (45) were isolated from the whole herb of Thalictrum cirrhosum 43 ( Figure 3). Hendersine B methyl ester (46), bicucullinine (47), and hendersine B (48) were isolated from C. tomentella.…”

“…44 Meanwhile, hernandezine (51), a known alkaloid, was identified from Thalictrum flavum. 45 In 2018, two secobisbenzylisoquinolines, 6,7,12-trimethoxy-2-methyl-13-hydroxy-11-(4′-formylphenoxy)benzylisoquinoline (52) and 5,6-(methylenedioxy)-7,12-dimethoxy-2-methyl-10-(4′-formylphenoxy)benzylisoquinoline (53), were isolated from Thalictrum wangii. 46 Tiliamosine (54) was found in Thalictrum racemosa 47 (Figure 3).…”

“…In this review, we list in Table 2 we found that most compounds exhibited moderate cytotoxicity with IC 50 values ranging from 10 to 50 μM. 22,25,27,33,38,40,45,46,53,68,80,[83][84][85][86][87][88]90,93,98,101,105,159 Three Amaryllidaceae alkaloids, lycorine (321), haemanthamine (326), and haemanthidine 327 Table 2. Higher antiproliferative effects also were reported.…”

Liquid chromatographic separation of alkaloids in herbal medicines: Current status and perspectives

“…Alkaloids are nitrogen atom‐containing basic compounds, which exist extensively in herbal medicines. Many of them have been demonstrated to possess a variety of pharmacological activities, and can serve as leading compounds for drug discovery due to desirable druggability [1]. Moreover, some alkaloids have been used in the clinic for the treatment of various diseases, such as ephedrine for bronchial asthma, berberine for diarrhea, and anisodamine for gastrointestinal colic.…”

Interaction Effects between Doxorubicin and Hernandezine on the Pharmacokinetics by Liquid Chromatography Coupled with Mass Spectrometry

“…Recent studies have shown that HER, as a new AMPK activator, could induce autophagy death in drug-resistant cancers [17]. Furthermore, HER could effectively inhibit the transport function of ABCB1 relative to MDR-linked ABC drug transporters ABCC1 and ABCG2 to enhance the drug-induced apoptosis of tumor cells [18].…”