• Archives of Pharmacal Research
• /
• v.29 no.9
• /
• pp.757-761
• /
• 2006

Six protoberberine alkaloids were isolated from the chloroform layer of the rhizome of Coptis japonica Makino (Ranunculaceae). The structures of the isolated compounds were determined to be 6-([1,3]dioxolo[4,5-g]isoquinoline-5-carbonyl)-2,3-dimethoxy-benzoic acid methyl ester (1), oxyberberine (2), 8-oxo-epiberberine (3), 8-oxocoptisine (4), berberine (5) and palmatine (6) by physicochemical and spectroscopic methods. The compound 3 (8-oxo-epiberberine) was first isolated from natural sources. The compounds were tested for cytotoxicity against five tumor cell lines in vitro by SRB method, and also tested for the MDR reversal activities. Compound 4 was of significant P-gp MDR inhibition activity with ED50 value $0.018\;{\mu}g/mL$ in MES-SA/DX5 cell and $0.0005\;{\mu}g/mL$ in HCT15 cell, respectively.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.8
• /
• pp.4635-4639
• /
• 2013

Multi-drug resistance (MDR) is an essential aspect of human lung cancer chemotherapy failure. Recent studies have shown that vinorelbine is involved in underlying processes in human tumors, reversing the MDR inseveral types of cancer cells. However, the roles and potential mechanism are not fully clear. In this study, we explored effects of vinorelbine in multi-drug resistance reversal of human lung cancer A549/DDP cells. We found that vinorelbine increased drug sensitivity to cisplatin and intracellular accumulation of rhodamine-123, while decreasing expression of P-glycoprotein (P-gp), multi-drug resistance-associated protein (MRP1) and glutathione-S-transferase ${\pi}$ (GST-${\pi}$) in A549/DDP cells. At the same time, we also established downregulation of p-Akt and decreased transcriptional activation of NF-${\kappa}B$ and twist after vinorelbine treatment. The results indicated that vinorelbine might be used as a potential therapeutic strategy in human lung cancer.

• Journal of Integrative Natural Science
• /
• v.4 no.1
• /
• pp.23-30
• /
• 2011

Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. MDR is associated with the over expression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents were limited by unacceptable toxicity, whereas second-generation agents had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on drug metabolism and no clinically significant drug interactions with common chemotherapy agents. Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.

• Bulletin of the Korean Chemical Society
• /
• v.32 no.12
• /
• pp.4444-4446
• /
• 2011

• Journal of Pharmaceutical Investigation
• /
• v.40 no.4
• /
• pp.255-261
• /
• 2010

Pluronic as pharmaceutical excipients are listed in the US and British Pharmacopoeia. In particular, Pluronics exist as different compositions and display abundant phases as self-assembling into polymeric micelles with various morphologies depending on the aqueous solvent quality, the composition of structure, and hydrophilic-lipophilic balance (HLB). Pluronics were also known as a P-gp modulator, which was exploited as a reversal molecule of multi-drug resistant (MDR) cancers. We selected a lamella forming Pluronic L92 which has high hydrophobicity and relatively long PEO block among L series of Pluronics. The dispersion of L92 showed great size particles and low stability. To increase the stability and to decrease the particle size, secondary Pluronics (F68, F88, F98, F127, P85, P105, and P123) with relatively long PEO chain were added into 0.1 wt% Pluronic L92 dispersion. The stability of binary systems was increased due to incorporated long PEO chain. Their particle sizes slightly decreased to over 200~400 nm and their solubilization capacity of binary systems didn't change except Pluronic L92/P123 mixtures. The L92/P123 systems showed ca. 100 nm sizes and lowest turbidity among the all systems. The solubilization capacity of 0.1 wt% L92/0.1 wt% P123 was slightly increased compared to 0.1 wt% L92 mono system and other binary systems. These nano-sized binary systems may have potential as alternative drug delivery systems with simple preparation method and overcome the drawbacks of mono systems such as low stability and loading capacity.

• Journal of Ginseng Research
• /
• v.44 no.2
• /
• pp.247-257
• /
• 2020

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.24
• /
• pp.10597-10601
• /
• 2015

Up-regulation of multidrug resistance-associated protein 1 (MRP1) is regarded as one of the main causes for multidrug resistance (MDR) of tumor cells, leading to failure of chemotherapy-based treatment for a multitude of cancers. However, whether silencing the overexpressed MRP1 is sufficient to reverse MDR has yet to be validated. This study demonstrated that RNAi-based knockdown of MRP1 reversed the increased efflux ability and MDR efficiently. Two different short haipin RNAs (shRNAs) targeting MRP1 were designed and inserted into pSilence-2.1-neo. The shRNA recombinant plasmids were transfected into cis-dichlorodiamineplatinum-resistant A549 lung (A549/DDP) cells, and then shRNA expressing cell clones were collected and maintained. Real time PCR and immunofluorescence staining for MRP1 revealed a high silent efficiency of these two shRNAs. Functionally, shRNA-expressing cells showed increased rhodamine 123 retention in A549/DDP cells, indicating reduced efflux ability of tumor cells in the absence of MRP1. Consistently, MRP1-silent cells exhibited decreased resistance to 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and DDP, suggesting reversal of MDR in these tumor cells. Specifically, MRP1 knockdown increased the DDP-induced apoptosis of A549/DDP cells by increased trapping of their cell cycling in the G2 stage. Taken together, this study demonstrated that RNAi-based silencing of MRP1 is sufficient to reverse MDR in tumor cells, shedding light on possible novel clinical treatment of cancers.

• Advances in Traditional Medicine
• /
• v.4 no.3
• /
• pp.179-185
• /
• 2004

The ethanol extract of Indigofera cordifolia was studied for in vivo gastroprotective activity, cytotoxic activity against oral tumor and normal cells, multidrug resistance (MDR) reversal activity, anti-human immunodeficiency virus (HIV) activity and radical scavenging activity. The extract of I. cordifolia showed potent gastric mucosal protective activity against stomach injury induced by HCl/EtOH solution. However, the gastroprotective activity could not be related to the radical mechanism, because the extract weakly scavenged both OH radical and $O_2*^-$. The extract also showed promising levels of MDR-reversing activity. This study demonstrates the tumor-specific cytotoxic action of the plant extract. However, the extract had no anti-HIV activity. From above results, the study suggests the medicinal importance of I. cordiforia extract.

• Proceedings of the PSK Conference
• /
• 2002.10a
• /
• pp.251.3-252
• /
• 2002

The present study was performed to compare the cardiovascular adverse effects of verapamil. KR30031 and their each optical isomers, and also to measure their ability to overcome multidrug resistance (MDR). R-isomer of KR30031 (R-KR30031) was equipotent with S-isomer of KR30031 (S-KR30031) and 25 fold less potent than R-isomer of verapamil (R-verapamil) in relaxing the aorta isolated from rat (EC50: 11.8, 10.2 and 0.46 ${\mu}$M, respectively). (omitted)

• Bulletin of the Korean Chemical Society
• /
• v.30 no.4
• /
• pp.779-780
• /
• 2009