Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

Pham, Anh-Nhan; Wang, Jeffrey; Fang, Jia‐Long; Gao, Xin; Zhang, Yilong; Blower, Paul E.; Sadée, Wolfgang; Huang, Ying

doi:10.1007/s11095-008-9796-8

Cited by 14 publications

(13 citation statements)

References 32 publications

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“…Methylation of certain promoter CpG islands predicts toxicity to antimetabolites and alkylating agents in the NCI-60 lines (Shen et al, 2007;Sasaki et al, 2008). Like HapMap LCLs, the NCI-60 panel has been important in examining the role of genetic variation in membrane transporters on sensitivity to chemotherapeutics (Huang et al, , 2005bSzaká cs et al, 2004;Liu et al, 2007a;Okabe et al, 2008;Pham et al, 2009). …”

Section: Nci-60 Cell-based Modelsmentioning

confidence: 99%

Pharmacogenomic Discovery Using Cell-Based Models

et al. 2009

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Section: Nci-60 Cell-based Modelsmentioning

confidence: 99%

Pharmacogenomic Discovery Using Cell-Based Models

et al. 2009

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“…As with many cancer therapeutics, resistance to 17AAG can result from increased efflux by the ABC transporter Pgp (18) or MRP1 (19). Pgp expression was significantly lower in capns1 Ϫ/Ϫ MEFs than in control capns1 ϩ/ϩ cells and was elevated in capns1 Ϫ/Ϫ / ⌬capns1 MEFs (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Interestingly, geldanamycins are both substrates and inhibitors of some ABC transporters, including Pgp (18). Pgp and MRP1 are implicated in the transport of 17AAG (18,19) and doxorubicin (32); the effect of MRP2 on 17AAG is unknown. Our data show that selected ABC trans- porters, specifically, Pgp in MEFs and MRP2 in MDA-MB-231 cells, have altered functions upon the loss of calpain, and this resulted in the increased cytotoxicity of drugs that are effluxed by these ABC transporters in calpain-deficient cells.…”

Section: Discussionmentioning

confidence: 99%

“…The antiproliferative and antitumor effects of 17AAG are well established across different tumor cell lines (16,17). Mechanistically, 17AAG induces both cell cycle arrest and apoptosis through its ability to inhibit HSP90 functions (16).HSP90 inhibitors, including 17AAG, may have limited use as monotherapies because of acquired resistance mediated in part by the expression of one or more ABC transporters, including multidrug resistance protein 1 (MRP1; ABCC1) and P glycoprotein (Pgp; ABCB1) (18,19). However, several clinical trials have demonstrated additive or synergistic effects when 17AAG is used in combination with existing targeted agents or chemotherapies, including trastuzumab (20), taxanes (21), and cisplatin (22).…”

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Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

Grieve

Gao

Hall

et al. 2016

Molecular and Cellular Biology

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Calpain is an intracellular Ca 2؉ -regulated protease system whose substrates include proteins involved in proliferation, survival, migration, invasion, and sensitivity to therapeutic drugs. Genetic disruption of calpain attenuated the tumorigenic potential of breast cancer cells and hypersensitized cells to 17AAG, an inhibitor of the molecular chaperone HSP90. Calpain-1 or -2 overexpression rendered cells resistant to 17AAG, whereas downregulation or inhibition of calpain-1/2 led to increased cell death in multiple breast cancer cell lines, including models of HER2 ؉ (SKBR3) and triple-negative basal-cell-like (MDA-MB-231) breast cancer. In an MDA-MB-231 orthotopic xenograft model, calpain knockdown or 17AAG treatment independently attenuated tumor growth and metastasis, while the combination was most effective. Calpain knockdown was associated with increased 17AAG-induced degradation of the HSP90 clients cyclin D1 and AKT and multidrug resistance protein 2, which correlated with increased expression of antimitogenic p27 KIP1 and proapoptotic BIM proteins. Like other therapeutics, 17AAG can be effluxed by specific ABC transporters. Calpain expression positively correlated with the expression of P glycoprotein in mouse embryonic fibroblasts. Importantly, we show that calpain affects ABC transporter function and efflux of clinically relevant doxorubicin. These observations provide a compelling rationale for exploring the combination of calpain inhibition with new or existing cancer therapeutics. Calpains are a family of intracellular calcium-dependent proteases. Of the 15 mammalian isoforms, calpain-1 and calpain-2 are ubiquitously expressed and have been most extensively studied (reviewed in reference 1). They are heterodimers consisting of isoform-specific catalytic subunits encoded by CAPN1 and CAPN2, respectively, and a common regulatory subunit encoded by CAPNS1. Heterodimerization is essential for both stability and enzymatic activity; hence, genetic disruption of CAPNS1 results in loss of both calpain-1 and -2 activities (2, 3).Elevated calpain expression or activity has been associated with multiple cancer types, including colon, liver, lung, prostate, ovarian, and breast cancers (reviewed in reference 4). Mechanistic understanding of calpain's involvement in cancer is confounded by its broad range of substrates, including signaling or structural proteins that regulate diverse cellular functions such as mitogenesis, migration, invasion, and death (1). Biomarker studies suggest a positive correlation between elevated calpain expression and a poor clinical outcome in breast cancer (5-7).Paradoxically, calpain is associated with prodeath (8, 9) or prosurvival (9-11), depending upon the physiologic context and specific challenges cells are exposed to. For example, calpain-mediated cleavage of PP2A supports activation of AKT and a prosurvival function in mouse embryonic fibroblasts (MEFs) (10), and in breast cancer cells and xenograft mouse models, knockdown of CAPN2 was associated with attenuated tumor growth...

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“…The dominant mechanism of MDR in a living cell lies in the active efflux of a broad range of anti-cancer drugs via the plasma membrane by MDR related proteins Chen et al, 2011;Sun et al, 2013). Upregulation of multidrug resistance-associated protein 1 (MRP1) is a well-defined phenotype during MDR (Pham et al, 2009;Yang et al, 2010;Ma et al, 2014). MRP1 belongs to a superfamily of ATP-binding cassette (ABC) transporters, members of which are associated with tumor resistance by increasing efflux ability and thus decreasing the intracellular accumulation of natural product anticancer drugs or other anticancer agents (Kepper., 2011).…”

Section: Introductionmentioning

confidence: 99%

RNAi-based Knockdown of Multidrug Resistance-associated Protein 1 is Sufficient to Reverse Multidrug Resistance of Human Lung Cells

Shao

Cui²,

Zhao³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Pharmacogenomics Approach Reveals MRP1 (ABCC1)-Mediated Resistance to Geldanamycins

Abstract: These results suggest that elevated expression of MRP1, like the alternative efflux transporter MDR1 (ABCB1, P-glycoprotein), can significantly influence tumor cell sensitivity to geldanamycins as a potential chemoresistance factor.

Cited by 14 publications

References 32 publications

Pharmacogenomic Discovery Using Cell-Based Models

Pharmacogenomic Discovery Using Cell-Based Models

Calpain Genetic Disruption and HSP90 Inhibition Combine To Attenuate Mammary Tumorigenesis

RNAi-based Knockdown of Multidrug Resistance-associated Protein 1 is Sufficient to Reverse Multidrug Resistance of Human Lung Cells

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