Multidrug Resistance Reversal Activity Research Articles

Pyrrolizine/indolizine-bearing (un)substituted isoindole moiety: design, synthesis, antiproliferative and MDR reversal activities, and in silico studies.

Two new series of pyrrolizine/indolizine derivative-bearing (un)substituted isoindole moiety were designed and synthesized. The anticancer potential of the new compounds was evaluated against hepatocellular carcinoma (HepG-2), colorectal carcinoma, colon cancer (HCT-116), and breast cancer (MCF-7) cell lines. Compounds 6d and 6o were the most potent derivatives with IC50 values ranging from 6.02 to 13.87 μM against HePG-2, HCT-116, and MCF-7 cell lines. Moreover, methyl analog of the fluoro-substituted indolizine derivative 6m revealed significant antiproliferative activity against HePG-2, HCT-116, and MCF-7 cancer cell lines with IC50 values of 11.97, 28.37, and 19.87 μM, respectively. The most active anticancer analogs, 6d, 6m, and 6o, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK 2) inhibitory activities. Thus, compound 6o displayed the most inhibitory activity against EGFR and CDK 2 with IC50 values of 62 and 118 nM, respectively. Additionally, the quantitative real-time PCR analysis for the P-glycoprotein effect of compounds 6d, 6m, and 6o was performed, in which compound 6o illustrated significant down-regulation of P-gp against the HepG-2 cell line by 0.2732 fold. Mechanistic studies for the most active compounds involving the reversal doxorubicin (DOX) effect of compounds 6d, 6m, and 6o were performed, which illustrated cytotoxic activity with IC50 22.27, 3.88, and 8.79 μM, respectively. Moreover, the apoptotic activity of the most active derivative 6o on HCT-116 cancer cells showed accumulation in the G1 and S phases of the cell cycle.

Meyeroguilline E, a New Isoindolinone Alkaloid from the Poisonous Mushroom Chlorophyllum molybdites, and Identification of Compounds with Multidrug Resistance (MDR) Reversal Activities.

Three isoindolinone alkaloids (1-3), including one new isoindolinone-type alkaloid, meyeroguilline E (1), and six other known compounds (4-9) were isolated from the poisonous mushroom Chlorophyllum molybdites (Agaricaceae). The structure of the new compound was determined using extensive spectroscopic analyses via one-dimensional (1D) and two-dimensional (2D) NMR data interpretation and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). To the best of our knowledge, compound 1 is the first example of a natural isoindolinone with a butanoic acid moiety, and this study is the first to detect the other known compounds (2-9) in C. molybdites. The isolated compounds (1-9) were examined for their multidrug resistance (MDR) reversal activity against MES-SA, MES-SA/DX5, HCT15, and HCT15/CL02 human cancer cells. Based on the results, 20 μM of compounds 3 and 6 slightly potentiated paclitaxel (TAX)-induced cytotoxicity in MES-SA/DX5, HCT15, and HCT15/CL02 cells; however, the compounds had no effect on the cytotoxicity against MES-SA and nonMDR cells.

Design, synthesis, and biological evaluation of ocotillol derivatives fused with 2-aminothiazole via A-ring as modulators of P-glycoprotein-mediated multidrug resistance

Overexpression of P-glycoprotein (P-gp) plays a key role in the development of multidrug resistance (MDR), the major reason for the failure of chemotherapy in clinics. Ocotillol and its derivatives had been reported with good P-gp-mediated tumor MDR reversal activity in vitro. Herein, a series of ocotillol derivatives fused with 2-aminothiazole (2-AT) via A-ring were designed and synthesized to further improve the tumor MDR reversal potency. These compounds were evaluated for their MDR reversal activity against the KBV cells by MTT assay. Among them, the most promising derivative against P-gp-mediated MDR was compound 12 with 2-AT and glycine in the A-ring. Rhodamine123 (Rh123) accumulation assay, Western blot assay, and P-gp-Glo™ assay showed that compound 12 efficiently inhibited the efflux function of P-gp by stimulating P-gp ATPase rather than downregulating its expression. Moreover, compound 12 sensitized KBV cells to paclitaxel arrested cells in the G2/M phase and induced cell apoptosis. Importantly, compound 12 significantly inhibited the growth of KBV cell-derived xenograft tumors in nude mice by increasing the sensitivity of paclitaxel in vivo. Finally, the structure-activity relationships (SARs) of ocotillol derivatives were further investigated. In summary, compound 12 has the potential to overcome MDR in cancer caused by P-gp.

The WD repeat-containing protein 5 (WDR5) antagonist WDR5-0103 restores the efficacy of cytotoxic drugs in multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2

The development of multidrug resistance (MDR) is one of the major challenges in the treatment of cancer which is caused by the overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and/or ABCG2 (BCRP/MXR/ABCP) in cancer cells. These transporters are capable of reducing the efficacy of cytotoxic drugs by actively effluxing them out of cancer cells. Since there is currently no approved treatment for patients with multidrug-resistant tumors, the drug repurposing approach provides an alternative route to identify agents to reverse MDR mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. WDR5–0103 is a histone H3 lysine 4 (H3K4) methyltransferase inhibitor that disrupts the interaction between the WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia (MLL) protein. In this study, the effect of WDR5–0103 on MDR mediated by ABCB1 and ABCG2 was determined. We found that in a concentration-dependent manner, WDR5–0103 could sensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to conventional cytotoxic drugs. Our results showed that WDR5–0103 reverses MDR and improves drug-induced apoptosis in multidrug-resistant cancer cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, without altering the protein expression of ABCB1 or ABCG2. The potential sites of interactions of WDR5–0103 with the drug-binding pockets of ABCB1 and ABCG2 were predicted by molecular docking. In conclusion, the MDR reversal activity of WDR5–0103 demonstrated here indicates that it could be used in combination therapy to provide benefits to a subset of patients with tumor expressing high levels of ABCB1 or ABCG2.

Microbial and chemical transformations of euphorbia factor L1 and the P-glycoprotein inhibitory activity in zebrafishes

Euphorbia factor L1 (EFL1, 1) is a natural tri-ester of 6,17-epoxylathyrol with cancer multidrug resistance (MDR) reversal activity. Several EFL1 derivatives (2–9) were prepared by chemical and microbial transformations and their ability to inhibit P-glycoprotein (P-gp) activity was estimated. Six de-acylated derivatives (2–7) were obtained through base-hydrolysis of 1, and the base-catalysed hydrolysis via KOH and NaOH yielded different hydrolysed products of 1. Two biotransformed products (8–9) were directly obtained via microbial transformation of 1, and 8 was also formed by microbial conversion of the hydrolysed product 3. The P-gp modulation of 1–9 was assessed by a zebrafish model. The substrate 1 and its biotransformed product 9 as the tri-esters of lathyranes possessed the highest P-gp inhibitory activity with IC50 values of 34.97 and 15.50 µM, respectively, through down-regulating P-gp expression at the protein level rather than at MDR1 mRNA level.

Six C21 steroidal glycosides from Cynanchum wallichii Wight roots and their multidrug resistance reversal activities

Six unidentified C21 steroidal glycosides, cynwallosides A−F, as well as twenty-two known compounds, were isolated from the roots of Cynanchum wallichii Wight. The structures of cynwallosides A−F were determined by spectroscopic analysis and acidic hydrolysis. Most of these twenty-eight compounds were found to significantly reverse drug resistance in both the MCF-7/ADR and HepG2/ADM cell lines by suppressing P-gp protein expression. Further investigation revealed that three compounds suppressed P-gp expression by significantly inactivating the JNK and NF-κB pathways.

Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles

The emergence of multidrug resistance (MDR) in tumors leads to reduced chemotherapeutic efficacy, and P-glycoprotein (P-gp) overexpression is one of the main causes of MDR. In previous reports, we demonstrated that a variety of hederagenin (HD) derivatives could reverse MDR in tumors in vivo and in vitro. To further enrich the structure types, enhance the activity, and improve the structure–activity relationships (SARs), three series of HD derivatives were designed and synthesized in this study via A-ring fusion and innovative utilization of the structural advantages of nitrogen-containing heterocycles and benzyl group substitution. We evaluated the MDR reversal activity of 21 HD derivatives in KBV (multidrug-resistant oral epidermoid carcinoma) cells and refined their SARs. The results of cell experiments illustrated that more than half of the compounds had MDR reversal activity. Among them, compound 16 displayed relatively stronger MDR reversal ability, as it improved the sensitivity of KBV cells to paclitaxel, vincristine, mitoxantrone and cisplatin with IC50 values of 3.19, 0.65, 125.30, and 4.54 nM, respectively. The results of mechanistic analysis demonstrated that compound 16 inhibited the efflux function of P-gp by activating P-gp ATPase and increased the accumulation of rhodamine 123 in KBV cells. Importantly, the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice was enhanced by compound 16 based on the growth suppression rate of 56.24%. These results indicated that introducing nitrogen-containing heterocycles could effectively improve the MDR reversal activity of HD derivatives, which appear to be promising lead compounds for tumor MDR reversal agent development.

Diterpenoids from Euphorbia glomerulans with potential reversal activities against P-glycoprotein-mediated multidrug resistance

The development of collateral sensitivity agents that are able to modulate P-glycoprotein (P-gp) is the most promising approaches to overcome multidrug resistance (MDR) in cancer. In this study, eight new diterpenoids of jatrophane and ingenane type, 1–8, and three known ones (9–11) were isolated from Euphorbia glomerulans. Their structures were elucidated by spectroscopic analysis and electronic circular dichroism (ECD) calculations. The MDR reversal activity evaluation of these isolates on breast cancer MCF-7/ADR cells demonstrated the four potent MDR modulators (3, 4, 5, and 9) with great chemoreversal ability and low cytotoxicity. The structure-activity relationship (SAR) analysis indicated that the presence of isobutanoyloxy group at C-8 significantly enhance reversal efficiency. Compound 5 exhibited high efficacy (EC50 = 159.5 nM) in reversing MDR resistance, being stronger than verapamil (EC50 = 302.9 nM). The MDR reversal mechanism assays revealed that 5 could promote the accumulation of Rh123 and DOX in drug-resistant cells in a certain dose-dependent manner, and inhibit P-gp transport function. In addition, the possible recognition mechanism of compound 5 and verapamil (VRP) with P-gp was predicted by molecular docking.

Chemical constituents from the flowers of Hypericum monogynum L. with COX-2 inhibitory activity

Hypericum monogynum L. (Hypericaceae) has been used as a folk Chinese medicine for the treatment of inflammatory related diseases. Cyclooxygenase-2 (COX-2) is a crucial target for the development of agents to treat inflammation. To search for anti-inflammatory compounds from traditional Chinese medicines, a chemical constituent study along with COX-2 inhibitory activity analysis was performed for this plant. In this study, sixteen chemical monomers, including three undescribed oxidative degradation polycyclic polyprenylated acylphloroglucinols (PPAPs, hypemoins C–E), two undescribed PPAPs (hypemoins A and B), and 11 known compounds, were identified from the flowers of H. monogynum. Their structures were characterized by HRESIMS, NMR techniques, ECD, and single crystal X-ray diffraction. Four flavonoid derivatives showed remarkable COX-2 inhibitory activities, with IC50 values ranging from 0.220 ± 0.006 to 1.655 ± 0.098 μM. Among these compounds, the possible recognition mechanism between quercetin 3-(6″-O-caffeoyl)-β-3-D-galactoside and COX-2 was predicted by molecular docking analysis. Moreover, the multidrug resistance reversal activities for the selected compounds were evaluated.

Bioactivities and Structure-Activity Relationships of Fusidic Acid Derivatives: A Review.

Fusidic acid (FA) is a natural tetracyclic triterpene isolated from fungi, which is clinically used for systemic and local staphylococcal infections, including methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. FA and its derivatives have been shown to possess a wide range of pharmacological activities, including antibacterial, antimalarial, antituberculosis, anticancer, tumor multidrug resistance reversal, anti-inflammation, antifungal, and antiviral activity in vivo and in vitro. The semisynthesis, structural modification and biological activities of FA derivatives have been extensively studied in recent years. This review summarized the biological activities and structure–activity relationship (SAR) of FA in the last two decades. This summary can prove useful information for drug exploration of FA derivatives.

Hypermonones A—I, New Polyprenylated Acylphloroglucinols from Hypericum monogynum with Multidrug Resistance Reversal Activity

Main observation and conclusionEleven biogenetically related polyprenylated acylphloroglucinols (PPAPs), including four novel skeletons (1—4) and five new compounds (5—9), were isolated from the flowers of Hypericum monogynum. Hypermonones A—D (1—4) represented the first example of a unique dilactone structure containing carbonyl bonded single δ‐lactone and tricyclic γ‐lactone moieties. Their structures were elucidated by NMR analysis, X‐ray crystallography, and ECD calculations. Moreover, we revised the structure of hyperibrin B to hypermonone I (9) via NMR analysis, a quantum computational chemistry method, and hypothetic biosynthetic considerations. Three compounds (5, 6, and 9) with significant MDR reversal activity (RF ranging from 61 to 223) were superior to the positive control verapamil (MCF‐7/ADR, RF: 53; HepG2/ADR, RF: 124). Mechanism study for compound 5 indicated that this compound could inhibit the function of P‐gp transport rather than its expression, and the possible recognition mechanism between compound 5 and P‐gp was predicted by molecular docking.

Synergistic Therapy of Doxorubicin with Cationic Anticancer Peptide L-K6 Reverses Multidrug Resistance in MCF-7/ADR Cancer Cells In Vitro via P-glycoprotein Inhibition

Multidrug resistance (MDR) is one of the major obstacles to efficient chemotherapy against cancers, resulting from the overexpression of drug efflux transporters such as P-glycoprotein (P-gP). In the present study, we aimed to evaluate the MDR reversal activity and synergistic therapeutic potential of cationic anticancer peptide L-K6 with doxorubicin (DOX) on P-gP-overexpressing and DOX-resistant MCF-7/ADR human breast cancer cells. Flow cytometry and confocal laser scanning microscopy were used to determine the intracellular accumulation of DOX and another P-gP substrate, Rho123. P-gP-Glo assay, Western blot and Biacore analysis were further performed to evaluate the P-gP function and expression. The cytotoxicity in MCF-7 or MCF-7/ADR cells was measured by MTT assay. Flow cytometry assay and confocal laser scanning microscopy observation clearly revealed an increased intracellular accumulation of DOX and Rho123 in MCF-7/ADR cells treated with L-K6, suggesting a P-gP inhibiting potential. Biacore analysis, P-gP-Glo assay and Western blot further confirmed that L-K6 could directly interact with P-gP, inhibit P-gP function and decrease P-gP expression in MCF-7/ADR cells. In addition, as expected, the data from MTT assay indicated that L-K6 restored the sensitivity of MCF-7/ADR cells to DOX, indicating a MDR reversal potential and a promising synergistic anticancer activity. All these findings may provide experimental evidence to support the promising applications and synergistic therapeutic potential of peptidic P-gP inhibitors against MDR cancer.

Mufolinin A, an unprecedented ring A-seco 10-ethyllimonoid from Munronia unifoliolata

Mufolinin A (1), a ring A-seco rearranged limonoid with an unprecedented ethyl at C-10 and novel 6/6/6/5 fused-ring skeleton, together with three new potential precursors (ring A-seco limonoids, 2–4) were isolated from Munronia unifoliolata. Their structures and absolute configurations were confirmed by nuclear magnetic resonance (NMR), high resolution electrospray ionization mass spectroscopy (HRESIMS), X-ray crystallography, electronic circular dichroism (ECD) calculations and NMR calculations with DP4+ analyses. The unprecedented ethyl group of 1 was hypothesized to be derived from methyl migration and ring reduction rearrangement of ring A-seco limonoid 4. Compounds 2 and 4 showed significant multidrug resistance (MDR) reversal activities in MCF-7/DOX cells with reversal fold (RF) values of 13.1 and 8.0, respectively.

Ingenane and jatrophane-type diterpenoids from Euphorbia kansui with multidrug resistance reversal activity

Bioassay-guided purification on the ethanolic extract of the roots of Euphorbia kansui Liou ex S.B.Ho (Euphorbiaceae) led to the isolation of one unreported ingenane-type (euphorksol A) and six unreported jatrophane-type (euphorksjats A−F) diterpenoids, together with twenty-five known diterpenoids. Their structures were elucidated based on extensive NMR analysis and high-resolution mass spectrometry. Euphorksol A is a rare example of an ingenane-type diterpenoid with a 6,7-expoxy fragment. All compounds were examined for cytotoxicity against adriamycin (Adr)-sensitive HepG-2 and Adr-resistant HepG-2/Adr cell lines, but none showed significant activity. Then, all isolates were evaluated for their ability to reverse multidrug resistance (MDR). 6β,7β-Epoxy-3β,4β,5β-trihydroxyl-20- deoxyingenol and 3,5,7,15-tetraacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11-diene showed significant MDR reversal activity in HepG-2/Adr cells (reversal fold: RF = 186.4 and 143.8, respectively) versus the positive control verapamil (Ver, RF = 93.7). Euphorksol A and kansuinin B exhibited moderate MDR reversal activity (RF = 57.4 and 68.9, respectively). These compounds are the first ingenane-type diterpenoids reported to show MDR reversal activity, which will provide new insights toward the development of MDR regulatory agents.

Jatrophane diterpenoids as multidrug resistance modulators from Euphorbia sororia

Eight new jatrophane diterpenoids, Euphosorophane F-M (1–8), as well as fourteen known jatrophane diterpenoids (9–22) were separated and purified from the fructus of Euphorbia sororia, and the chemical structures were determined based on extensive spectroscopic analysis, 1D, 2D NMR and HRESIMS data included. Their absolute configurations of compounds 1, 2, 9, and 22 were elucidated by X-ray crystallographic analysis. These jatrophane diterpenoids showed lower cytotoxicity and compounds 3, 4, 11, 12, 13, 14, and 20 revealed promising multidrug resistance (MDR) reversal ability as modulators compared to verapamil (VRP) by MTT assay. The structure–activity relationship (SAR) exhibited that the absence of keto-carbonyl at C-9 and C-14 was essential to MDR reversal activity and the acyloxies substitution at C-5, C-7, C-8, and C-14 also made the activity difference. Euphosorophane I (4) particularly unfold greater potency (EC50 = 1.82 μM) in reversing P-gp-mediated resistance to doxorubicin (DOX). As shown by fluorescence microscopy, 4 promoted intracellular accumulation of rhodamine 123 (Rh123) and DOX in a dose-dependentmanner than VRP. Flow cytometry indicated that 4 inhibitedP-glycoprotein (P-gp) -dependentRh123 efflux in drug-resistant MCF-7/ADR cells. 4 stimulated P-gp-ATPase activity in a concentration-dependent way and inhibited DOX transport activity. Western blot and real-time qPCR results further illustrated that 4 exhibited superior MDR reversal effect in MCF-7/ADR cells attributed to the activation of ATPase rather than the upregulation of P-gp expression and mRNA levels. In addition, 4 bond to the drug-binding site of P-gp predicted by the molecular docking analysis. Collectively, these results indicated that 4 efficiently reversed P-gp-mediated MDR via inhibiting the ABCB1 drug efflux function. 4 with the advantage of low toxicity and efficient could be used as an adjuvanttherapy drug for breast cancer.

Discovery of new pyrimidopyrrolizine/indolizine-based derivatives as P-glycoprotein inhibitors: Design, synthesis, cytotoxicity, and MDR reversal activities.

Targeting P-glycoprotein (P-gp, ABCB1 transporter), which plays an essential role in multi-drug resistance (MDR) in cancers, with new cytotoxic agents is a promising strategy in cancer chemotherapy. In the current study, we report the synthesis of thirteen novel pyrimidopyrrolizine, pyrimidoindolizine, and diazepinopyrrolizine derivatives. The new compounds exhibited cytotoxic activities against MCF7, A2780 and HT29 cancer cell lines (IC50=0.02-19.58μM) and MRC5 (IC50=0.17-20.57 μM). The six most active compounds (23b, 24a,b and, 31c-e) were evaluated for their MDR reversal activities in MCF7/ADR cells. Mechanistic study using real-time PCR revealed the ability of compound 31c to inhibit P-gp. In addition, compound 31c increased the accumulation of Rho123 inside MCF7/ADR cells in a dose-dependent manner compared to verapamil. Compound 31c arrested the cell cycle of MCF7 cells at the G1 phase. Compound 31c also caused a significant dose-dependent increase of early and late apoptotic events. Molecular docking analysis revealed a high binding affinity for compound 31c toward P-gp. Like zosuquidar, compound 31c displayed one hydrogen bond and several hydrophobic interactions with amino acids in P-gp. These results indicated that compound 31c represents a potential anticancer candidate with MDR reversal activity.

Dihydro-β-agarofuran-Type Sesquiterpenoids from the Seeds of Celastrus virens and Their Multidrug Resistance Reversal Activity against the KB/VCR Cell Line.

Twenty-nine dihydro-β-agarofuran-type sesquiterpenoids, including 17 new and 12 known compounds, were obtained from the seeds of Celastrus virens. The structures of the new isolates were characterized by spectroscopic methods and X-ray diffraction analysis. Among these, 20 sesquiterpenoids were evaluated for their multidrug resistance (MDR) reversal activity against the KB/VCR cell line. As a result, compounds 6 and 8 were found to exhibit MDR-reversal activity of more than 10-fold at a concentration of 2 μM, and the reversal fold (RF) ratios of compounds 19, 21, and 24 were >97.9 at a 20 μM nontoxic concentration level.

Two new seco-polycyclic polyprenylated acylphloroglucinol from Hypericum sampsonii.

Hypsampsone A (1) and hyperhexanone F (2), two novel seco-polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum sampsonii. Hypsampsone A (1) features the first spirocyclic system fused with 5/6/5/5 tetracyclic skeleton. Hyperhexanone F (2) represents the second novel 1,2-seco-bicyclo[3.3.1]-PPAP skeleton. Their structures were established by extensive spectroscopic analysis, computer-assisted structure elucidation software, and calculated electronic circular dichroism spectra. A plausible biogenetic pathway of 1 was also proposed. Compounds 1 and 2 showed moderate multidrug resistance reversal activity to adriamycin (ADR) resistant cancer cell lines, HepG2/ADR and MCF-7/ADR, with the fold-reversals ranging from 16 to 38 at noncytotoxic concentration of 10 μM.

Design, synthesis, and biological evaluation of hederagenin derivatives with improved aqueous solubility and tumor resistance reversal activity.

Multidrug resistance (MDR) has become a major obstacle to malignancies treatment by chemotherapeutic drugs, therefore, it is important to develop MDR reversal agents with high activity. We have previously found that the hederagenin (HD) derivative HBQ showed good tumor MDR reversal activity invitro and invivo but had poor solubility. In this study, to enhance the aqueous solubility and tumor MDR reversal activity of HBQ, three series of HD derivatives were designed and synthesized. Nitrogen-containing heterocyclic-substituted, PEGylated, and ring-A substituted derivatives significantly reversed the MDR phenotype of KBV (multidrug-resistant oral epidermoid carcinoma) cells toward paclitaxel at a concentration of 10μM in MTT assays. The PEGylated derivatives 10c-10e had increased aqueous solubility compared with HBQ by 18-657 fold, while maintaining tumor MDR reversal activity. The most invitro active compound 10c possessed good chemical stability to an esterase over 24h and enhanced the sensitivity of KBV cells to paclitaxel and vincristine with IC50 values of 4.58 and 0.79nM, respectively. Mechanism studies indicated that compound 10c increased the accumulation of P-glycoprotein (P-gp) substrates rhodamine 123 and Flutax1 in KBV cells and MCF-7T (paclitaxel-resistant breast carcinoma) cells, that is to say, compound 10c exerted the reversal effect of tumor MDR by inhibiting the efflux function of P-gp. Finally, the structure-activity relationships were further investigated by analyzing the relationship between structure and tumor MDR reversal activity of HD derivatives. This study highlights the potential of PEGylated HD derivatives such as compound 10c for the development of tumor MDR reversal agents and provides information for the further improvement of the aqueous solubility and tumor MDR reversal activity of HD derivatives in the future.

Tetrandrine partially reverses multidrug resistance of human laryngeal cancer cells.

ObjectiveStudies have demonstrated that tetrandrine reverses multidrug resistance (MDR) in animal models or cell lines derived from multiple cancer types. We examined the potential MDR reversal activity of tetrandrine in a multidrug-resistant variant of a human laryngeal cancer Hep-2 cell line and explored potential mechanisms involved.MethodsWe developed the multidrug-resistant variant cell line (Hep-2/v) by exposing Hep-2 cells to stepwise increasing concentrations of vincristine (VCR). After Hep-2 or Hep-2/v cells were treated with tetrandrine (2.52 µg/mL), MDR was measured by MTT assay, rhodamine 123 retention was measured by flow cytometry, and mRNA and protein expression of multidrug resistance 1 (MDR1), regulator of G-protein signaling 10 (RGS10), high-temperature requirement protein A1 (HTRA1), and nuclear protein 1 (NUPR1) were detected by real-time reverse transcription-PCR and western blotting, respectively.ResultsTetrandrine significantly lowered the half-maximal inhibitory concentration (IC50) of VCR in Hep-2/v cells, resulting in a 2.22-fold reversal of MDR. Treatment with tetrandrine increased rhodamine 123 retention, downregulated the mRNA and protein expression of MDR1 and RGS10, and upregulated expression of HTRA1 in Hep-2/v cells.ConclusionWe showed that tetrandrine exerts anti-MDR activity in Hep-2/v cells, possibly by inhibiting MDR1 overexpression-mediated drug efflux and by altering expression of HTRA1 and RGS10.