Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro

Peigñan, Lilia; Garrido, Wallys; Segura, Rodrigo; Melo, Rómulo; Rojas, David; Cárcamo, Juan G.; Martin, R. H.; Quezada, Claudia

doi:10.1007/s11064-011-0464-8

Cited by 37 publications

(44 citation statements)

References 55 publications

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“…Because of the relative differences in effect based on methylation status (and HFE genotype) we investigate CC-I in combination with TMZ and found the addition of CC-I improves TMZ efficacy in TMZ resistant astrocytoma cell lines. These findings are consistent with several studies reporting a combination effect with an anti-tumor compound and TMZ in TMZ resistant astrocytoma cell lines [51], [52]. The data suggest that CC-I could be considered an adjuvant therapy with TMZ.…”

Section: Discussionsupporting

confidence: 92%

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

et al. 2014

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The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I. There is a dose-dependent cytotoxic effect of CC-I in TMZ resistant astrocytoma cells. Cell death appears to occur via apoptosis. Following CC-I exposure, there was an increase in astrocytoma cells in the S and G2/M phases. In in vivo athymic (nu/nu) nude mice subcutaneous and intracranial tumor models, CC-I completely inhibited tumor growth without liver or kidney toxicity. Molecular modeling and enzyme activity assays indicate that CC-I selectively inhibits topoisomerase IIα similar to other drugs in its class, but its cytotoxic effects on astrocytoma cells are stronger than these compounds. The cytotoxic effect of CC-I is stronger in cells expressing unmethylated O6-methylguanine methyltransferase (MGMT) but is still toxic to cells with methylated MGMT. CC-I can also enhance the toxic effect of TMZ on astrocytoma when the two compounds are combined. In conclusion, we have identified a compound that is effective against astrocytomas including TMZ resistant astrocytomas in both cell culture and in vivo brain tumor models. The enhanced cytotoxicity of CC-I and the safety profile of this family of drugs could provide an interesting tool for broader evaluation against brain tumors.

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Section: Discussionsupporting

confidence: 92%

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

et al. 2014

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“…In their findings they list that temozolomide is a substrate for Pgp and Breast cancer related protein (BCRP) but not MRP1. Additionally, our findings corroborate Peignan et al (2011), who note a lack of effect on cell death in the commercial GBM line T98G when MRP1 siRNA was used in vitro .…”

Section: Discussionsupporting

confidence: 91%

Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

et al. 2015

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Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30–40% response rate, many fall into the range of 10–20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.

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“…Accordingly, our results showed that the ATP-dependent efflux transporter Mrp1 was highly expressed in NS, following by a decrease along differentiation. Regarding GL261 cells, the levels of Mrp1 expression were also very high, such as previously detected in glioma samples and in glioma cell lines [61,62] . Since Mrp1 expression is significantly up-regulated in cancer stem-like cells (CD133+ cells), isolated from GBM [63] , and given that these undifferentiated tumor cells share some properties with 86 www.ommegaonline.org…”

Section: Discussionsupporting

confidence: 65%

Early Differentiating Mouse Astroglial Progenitors Share Common Protein Signatures with GL261 Glioma Cells

Brites¹

2016

JSRB

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Neural stem cells (NSC) biology is being applied to tumor research because these cells have been shown to share key properties with cancer cells. Gliomas represent the most common brain tumor, and neural stem/progenitor cells (NSPC) or early-differentiated cell type lineages may be on its origin. Here, we identified the developmental stage of the differentiation process of NSC into astrocytes that showed the highest number of tumorigenic similarities.NSPC were grown as neurospheres and astroglial differentiation was induced during 7 days in vitro (DIV). Cellular characterization was evaluated by specific neural markers at two developmental windows, i.e. NSPC/astrocyte progenitors from neurospheres until 3 DIV, and differentiating astrocytes thereafter. Predominance of immature Sox2-positive cells was verified in the first window and a prevalence of GFAP-positive cells in the second one. We then compared some tumor-related markers in GL261 glioma cells with such differentiating periods. The early progenitor cells (until 2 DIV) were those with the closest resemblances to the glioma cell line regarding BrdU incorporation, expression of microtubule-associated protein light chain 3 and of angiogenic factors (VEGF/VEGFR2), as well as S100B release. Our results suggest that early differentiating astroglial progenitors may be more susceptible to malignant transformation.

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Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro

Cited by 37 publications

References 55 publications

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

Characterization of a Novel Anti-Cancer Compound for Astrocytomas

Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme

Early Differentiating Mouse Astroglial Progenitors Share Common Protein Signatures with GL261 Glioma Cells

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