Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells

Sato, Hiromi; Siddig, Sana; Uzu, Miaki; Suzuki, Sayumi; Nomura, Yuki; Kashiba, Tatsuro; Gushimiyagi, Keisuke; Sekine, Yuko; Uehara, Tomoya; Arano, Yasushi; Yamaura, Katsunori; Ueno, Koichi

doi:10.1016/j.ejphar.2014.11.021

Cited by 32 publications

(28 citation statements)

References 26 publications

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“…The introduction of tyrosine-kinase inhibitors (TKIs) was considered as a breakthrough in the treatment of metastatic RCC [16–18]. However, most metastatic RCC patients administrated with TKIs eventually yield to disease progression due to drug resistance [19]. Several studies have been initiated in an attempt to discover reliable prognostic biomarkers to predict the overall survival of RCC patients.…”

Section: Discussionmentioning

confidence: 99%

ABCG2 is a potential prognostic marker of overall survival in patients with clear cell renal cell carcinoma

et al. 2017

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BackgroundATP-binding cassette sub-family G member 2 (ABCG2) is a semi-transport protein that plays a major role in multidrug resistance. We aimed to evaluate the prognostic significance of ABCG2 expression in patients with clear cell renal cell carcinoma.MethodsFrom 2008 to 2013, 120 patients with clear cell kidney cancer underwent surgery with paraffin-embedded specimens and necessary clinical information available. Immunohistochemistry staining was performed to grade the expression of ABCG2 as ABCG2(−): less than 10% of tumor cells stained; ABCG2(+): weak membrane staining; and ABCG2(++): moderate or strong membrane staining. The overall survival was analyzed using Kaplan-Meier method. Multivariable Cox regression evaluated the independent predictors for overall survival.ResultsABCG2(−) was diagnosed in 57 (48%) patients, ABCG2(+) in 52 (43%) patients, and ABCG2 (++) in 11(9.2%) patients. ABCG2 expression significantly correlated with the five-year survival (p < 0.001) and distant metastasis (p = 0.001). In the multivariable analysis, besides Fuhrman grade, the ABCG2 expression was an independent prognostic marker for overall survival (p < 0.001) when incorporating other relevant tumor and clinical parameters (HR = 3.84, 95% CI: 1.92–7.70).ConclusionThe current data suggests that ABCG2 may serve as a prognostic marker for overall survival in patients with clear cell renal cell carcinoma. Further studies with large cohorts of patients will be essential for validating these findings and defining the clinical utility of ABCG2 in the patient population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3224-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

ABCG2 is a potential prognostic marker of overall survival in patients with clear cell renal cell carcinoma

et al. 2017

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“…In these cells, P-gp was reported to be highly expressed in 786-O cells but not in MCF-7 cells [1,21]. Then, the possibility of Jaspine B being a substrate for efflux pumps such as P-gp and BCRP was investigated.…”

Section: Discussionmentioning

confidence: 99%

“…In spite of the overexpression of sphingosine kinase, the sensitivity of Jaspine B varied over 12.7-fold and MBA-MD-231 cells were resistant to it. It was hypothesized that the differential sensitivity of different cancer cells to Jaspine B could be due to the differences in the cellular accumulation of Jaspine B as efflux pumps such as P-glycoprotein and BCRP have often been obstacles to cancer chemotherapy by decreasing the cellular accumulation of structurally diverse cancer drugs in various cancers [1,21]. Indeed, the cellular accumulation could be a factor responsible for the differential cytotoxic effects of Jaspine B, which was demonstrated by the significant reciprocal correlation between EC50 values and the intracellular levels of Jaspine B in different cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Involvement of efflux pumps in Jaspine B transport As the overexpression of P-gp in MDA-MB-231 and 786-O cells has been reported to be related to resistance to anti-cancer drugs and P-gp was highly expressed in 786-O cells but not in MCF-7 cells [1,21], the effect of P-gp on the efflux of Jaspine B, as well as its ability to modulate the intracellular concentration of Jaspine B was investigated.…”

Section: Methodsmentioning

confidence: 99%

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Differential Cytotoxic Effects of Jaspine B in Various Cancer Cells

Lee¹,

Choi²,

Kwon³

et al. 2016

Journal of Life Science

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Jaspine B is an anhydrophytosphingosine that is isolated from a marine sponge. Because of its structural similarity to sphingosine, it shows anti-cancer effects in human carcinomas. Therefore, this study aims to investigate its anti-proliferative effect on various cancer cells and to correlate its association with the intracellular accumulation of Jaspine B in relevant cancer cells. The anti-proliferative effect of Jaspine B in various cancer cells was determined by a cell viability test, and the intracellular concentration of Jaspine B in relevant cancer cells was determined using mass spectrometry coupled with liquid chromatography. The correlation coefficient and p value between the cytotoxicity and the cell accumulation of Jaspine B were determined using SPSS 16.1. The cytotoxicity of Jaspine B varied depending on the type of cancer cell when compared the EC50 values of Jaspine B. Breast and melanoma cancer cells were susceptible to Jaspine B, whereas renal carcinoma cells were resistant. The intracellular concentrations of Jaspine B had a reciprocal correlation with the EC50 values in the same cells (r = 0.838). The results suggested that the anti-proliferative effect of Jaspine B was associated with the cellular accumulation of this compound. However, Jaspine B was not a substrate for P-glycoprotein and breast cancer resistance protein, as major efflux pumps caused multidrug resistance. The maintenance of a high intracellular concentration is crucial for the cytotoxic effect of Jaspine B; however, efflux pumps may not be a controlling factor for Jaspine B-related resistance in cancer cells.

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“…As angiogenesis is one of the distinct hallmarks of cancer, antiangiogenic cancer therapy is emerging as a promising strategy to combat drug resistance. [1][2][3] Several antiangiogenic drugs have been approved by the U.S. Food and Drug Administration and successfully translated into the clinical context for various cancers. [4][5][6] There are several advantages of targeting endothelial cells (ECs) to inhibit tumor angiogenesis compared with conventional chemotherapy, which directly targets cancer cells to inhibit their proliferation or induce their death.…”

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confidence: 99%

IF7-Conjugated Nanoparticles Target Annexin 1 of Tumor Vasculature against P-gp Mediated Multidrug Resistance

Liu

Luan

et al. 2015

Bioconjugate Chem.

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Multidrug resistance is the main cause of clinical chemotherapeutic failure. Antiangiogenic cancer therapy with nanomedicine that allows the targeted delivery of antiangiogenic agents to tumor endothelial cells may contribute to innovative strategies for treating multidrug-resistant cancers. In this study, we developed a new nanodrug delivery system (nano-DDS), with improved antiangiogenic efficacy against multidrug resistant human breast cancer MCF-7/ADR cells. Here, the IF7 ligand was a peptide designed to bind the annexin 1 (Anxa 1), a highly specific marker of the tumor vasculature surface, with high affinity and specificity. IF7-conjugated Anxa 1-targeting nanoparticles containing paclitaxel (IF7-PTX-NP) allowed controlled drug release and displayed favorable prolonged circulation in vivo. IF7-PTX-NP was significantly internalized by human umbilical vein endothelial cells (HUVEC) through the IF7-Anxa 1 interaction, and this facilitated uptake enhanced the expected antiangiogenic activity of inhibiting HUVEC proliferation, migration, and tube formation in a Matrigel plug relative to those of Taxol and PTX-NP. As IF7-PTX-NP targeted the tumor vessels, more nanoparticles accumulated in MCF-7/ADR tumors, and more importantly, induced significant apoptosis of the tumor vascular endothelial cells and necrosis of the tumor tissues. Low dose paclitaxel (1 mg/kg) formulated in IF7-PTX-NP showed significant anticancer efficacy, delaying the growth of MCF-7/ADR tumors. The same efficacy was only obtained with an 8-fold dose of paclitaxel (8 mg/kg) as Taxol plus XR9576, a potent P-gp inhibitor. The anticancer efficacy of IF7-PTX-NP was strongly associated with the improved antiangiogenic effect, evident as a dramatic reduction in the tumor microvessel density and pronounced increase in apoptotic tumor cells, with no obvious toxicity to the mice. This nano-DDS, which targets the tumor neovasculature, offers a promising strategy for the treatment of multidrug-resistant cancer.

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Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells

Cited by 32 publications

References 26 publications

ABCG2 is a potential prognostic marker of overall survival in patients with clear cell renal cell carcinoma

ABCG2 is a potential prognostic marker of overall survival in patients with clear cell renal cell carcinoma

Differential Cytotoxic Effects of Jaspine B in Various Cancer Cells

IF7-Conjugated Nanoparticles Target Annexin 1 of Tumor Vasculature against P-gp Mediated Multidrug Resistance

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