Utility of P-Glycoprotein and Organic Cation Transporter 1 Double-Transfected LLC-PK1 Cells for Studying the Interaction of YM155 Monobromide, Novel Small-Molecule Survivin Suppressant, with P-Glycoprotein

Iwai, Miwako; Minematsu, Tsuyoshi; Li, Qun; Iwatsubo, Takafumi; Usui, Takashi

doi:10.1124/dmd.111.040733

Cited by 46 publications

(42 citation statements)

References 30 publications

(32 reference statements)

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“…Considering the low passive permeability of NC, MDCK-MDR1 cells may not be suitable for assessing the interaction of NC with MDR1. A similar phenomenon was observed by Iwai et al, (2011), who found that OCT1/MDR1 double-transfected LLC-PK1 cells were more suitable than MDCK-MDR1 cells for studying the interaction between MDR1 and the OCT1 substrates with low passive permeability. Therefore, the OCT1/MDR1 double-transfected MDCK cells would be required to elucidate the interaction of NC with MDR1.…”

Section: Discussionsupporting

confidence: 54%

The Contribution of Human OCT1, OCT3, and CYP3A4 to Nitidine Chloride–Induced Hepatocellular Toxicity

Yang

et al. 2014

Drug Metab Dispos

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Nitidine chloride (NC), a quaternary ammonium alkaloid, has numerous pharmacological effects, such as anticancer activity. However, it was found that NC also has hepatocellular toxicity. Because organic cation transporters 1 and 3 (OCT1 and OCT3) might mediate the influx of NC into hepatocytes, multidrug and toxin extrusion 1 (MATE1) probably mediates the efflux of NC from hepatocytes, while cytochrome P450 (P450) enzymes might contribute to NC metabolism, the present study was to evaluate the contribution of OCT1, OCT3, MATE1, and P450 enzymes to NCinduced hepatocellular toxicity. Our results showed that the uptake of NC in Madin-Darby canine kidney (MDCK) cells expressing human (h) OCT1 and OCT3 (MDCK-hOCT1 and MDCK-hOCT3) was significantly higher than that in mock cells; the hOCT1-and hOCT3-mediated uptake followed typical Michaelis-Menten kinetics.Meanwhile, NC was also a substrate of hMATE1, although its transport capacity was much lower than that of OCT1 NC-induced cytotoxicity in MDCK-hOCT1 or MDCK-hOCT3 cells was obviously higher than that in mock cells. Quinidine and (+)-tetrahydropalmatine [(+)-THP], OCT1 and OCT3 inhibitors, significantly reduced the uptake of NC in MDCK-hOCT1 cells, MDCK-hOCT3 cells, and rat primary hepatocytes, but only (+)-THP markedly attenuated the NCinduced toxicity. In addition, P450 enzymes, such as CYP3A4, mediated the metabolism of NC, and NC-induced toxicity in MDCKhOCT1/hCYP3A4 cells was lower than that in MDCK-hOCT1 cells. Our results indicated that NC is a substrate of hOCT1, hOCT3, and CYP3A4; that OCT1 and OCT3 mediate the uptake of NC in hepatocytes and subsequently cause hepatotoxicity; and that NC-induced toxicity could be attenuated by CYP3A4-mediated metabolism.

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Section: Discussionsupporting

confidence: 54%

The Contribution of Human OCT1, OCT3, and CYP3A4 to Nitidine Chloride–Induced Hepatocellular Toxicity

Yang

et al. 2014

Drug Metab Dispos

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“…25) Transportation of YM155 across the cell membrane likely involves the organic cation transporters OCT1 and OCT2 and multidrug resistance protein 1 (MDR1). [26][27][28] MDR1 also effluxes taxanes and is related with drug resistance to taxanes. 29) We therefore hypothesized that efflux of YM155 from cancer cells is affected by taxanes, resulting in increased concentrations of YM155 in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Antitumor Activities of Sepantronium Bromide (YM155), a Survivin Suppressant, in Combination with Microtubule-Targeting Agents in Triple-Negative Breast Cancer Cells

Kaneko

Yamanaka

Kita

et al. 2013

Biological & Pharmaceutical Bulletin

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Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes, and effective treatment options are limited to cytotoxic agents, including microtubule-targeting agents, due to the lack of molecular targets. Here, we examined the combined effect of sepantronium bromide (YM155) and microtubule-targeting agents in TNBC models. The combination of YM155 with docetaxel showed synergistic antiproliferative and caspase 3/7-inducing effects in MRK-nu-1 and MDA-MB-453 human TNBC cell lines in vitro. YM155 also synergistically enhanced the efficacies of other microtubule-targeting agents, including paclitaxel and vinorelbine, which induced accumulation of survivin at the G2/M phase, whereas it did not affect the efficacy of doxorubicin. Combination treatment with YM155 and microtubule-targeting agents decreased the accumulation of survivin at the G2/M phase and induced greater apoptosis than either single agent alone. Further, combination treatment with YM155 and docetaxel also had a synergistic antitumor effect, achieving complete regression without exacerbation of body weight loss in all mice, in a MRK-nu-1 human TNBC xenograft model. These results suggest that survivin inhibition synergistically sensitize human TNBC cells to microtubule-targeting agents. Key words survivin; YM155; microtubule-targeting agent; triple-negative breast cancerBreast cancer is the second leading cause of cancer death among women in the United States.1) Triple-negative breast cancer (TNBC) is a clinical phenotype characterized by a lack of estrogen receptor (ER) and progesterone receptor (PR) expression as well as an absence of human epidermal growth factor-2 (HER-2) overexpression. Retrospective studies show that TNBC represents approximately 15% of total breast cancers and suggest that this cancer type is aggressive, with rapid tumor growth, a high incidence of metastasis, an increased possibility of distant recurrence, and a higher mortality rate than other breast cancers.2-4) Unlike patients with an ER/ PR-positive or HER-2-overexpressing subtype, this lack of molecular targets limits systemic treatment options for patients with TNBC to cytotoxic chemotherapy. Among them, microtubule-targeting agents, such as taxanes and vinca alkaloids are one of the most common class of chemotherapeutic drugs for the treatment of TNBC. 5,6) Despite the sensitivity of TNBC to chemotherapy, however, prognosis remains poor. The median time to death was shorter in patients with TNBC than in those with other subtypes. 7) Moreover, patients with TNBC who had residual disease after neoadjuvant chemotherapy had a particularly poor outcome.8) This poor prognosis and lack of therapeutic agents has underscored the demand for novel therapeutic options and strategies.Survivin, a member of the inhibitor of apoptosis (IAP) family of proteins, has been implicated in both cell survival and regulation of mitosis. 9) Overexpression of survivin is observed in various types of cancer, including breast cancer.10,11) Inhibition of survivin using ribozyme ...

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“…However, no IAP inhibitors have been approved by the U.S. Food and Drug Administration as of today, and there are limitations with many existing IAP inhibitors. For example, YM155 is a well-known survivin inhibitor that has gone through clinical trials, but it has been shown to be a substrate for the P-glycoprotein (P-gp) drug efflux pump (Iwai et al, 2011), suggesting that it could suffer from multidrug resistance (MDR) in its eventual clinical use. Thus, exploring novel scaffolds to develop potent and selective IAP antagonists is still much needed.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Second Mitochondria-Derived Activator of Caspase Mimetics as Selective Inhibitor of Apoptosis Protein Inhibitors

Wang

2014

J Pharmacol Exp Ther

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Inhibitor of apoptosis (IAP) proteins are widely considered as promising cancer drug targets, especially for drug-resistant tumors. Mimicking the IAP-binding motif of second mitochondriaderived activator of caspases (SMAC) is a rational strategy to design potential IAP inhibitors. In this report, we used the bioactive conformation of AVPI tetrapeptide in the N terminus of SMAC as a template and performed a shape-based virtual screening against a drug-like compound library to identify novel IAP inhibitors. Top hits were subsequently docked to available IAP crystal structures as a secondary screening followed by validation using in vitro biologic assays. Four novel hit compounds were identified to potently inhibit cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines. The best compound, UC-112[5-((benzyloxy)methyl)-7-(pyrrolidin-1-ylmethyl)quinolin-8-ol], has IC 50 values ranging from 0.7 to 3.4 mM. UC-112 also potently inhibits the growth of P-glycoprotein (P-gp)-overexpressed multidrug-resistant cancer cells, strongly activates caspase-3/7 and caspase-9 activities, and selectively downregulates survivin level at a concentration as low as 1 mM. Coincubation of UC-112 with a known proteasome inhibitor Z-Leu-Leu-Leu-CHO (MG-132) rescued survivin inhibition, consistent with the anticipated mechanism of action for UC-112. As a single agent, UC-112 strongly inhibits tumor growth and reduces both X chromosomelinked IAP and survivin levels in an A375 human melanoma xenograft model in vivo. Overall, our study identified novel scaffolds, especially UC-112, as new platforms on which potent and selective IAP antagonists can be developed.

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Utility of P-Glycoprotein and Organic Cation Transporter 1 Double-Transfected LLC-PK1 Cells for Studying the Interaction of YM155 Monobromide, Novel Small-Molecule Survivin Suppressant, with P-Glycoprotein

Cited by 46 publications

References 30 publications

The Contribution of Human OCT1, OCT3, and CYP3A4 to Nitidine Chloride–Induced Hepatocellular Toxicity

The Contribution of Human OCT1, OCT3, and CYP3A4 to Nitidine Chloride–Induced Hepatocellular Toxicity

Synergistic Antitumor Activities of Sepantronium Bromide (YM155), a Survivin Suppressant, in Combination with Microtubule-Targeting Agents in Triple-Negative Breast Cancer Cells

Discovery of Novel Second Mitochondria-Derived Activator of Caspase Mimetics as Selective Inhibitor of Apoptosis Protein Inhibitors

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