Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Lagas, Jurjen S.; Waterschoot, Robert A.B. van; Sparidans, Rolf W.; Wagenaar, Els; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1158/1535-7163.mct-09-0663

Cited by 168 publications

(132 citation statements)

References 35 publications

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“…However, most of them have been showed to be substrates of Pgp and/ or BCRP (29)(30)(31)(32)(33)(34), and are likely to exert their effects only in areas where the BBB or blood-tumor barrier is permeable, as described by Taskar and colleagues with lapatinib (35).…”

Section: Discussionmentioning

confidence: 99%

Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

Salphati

Heffron²,

Alicke³

et al. 2012

Clinical Cancer Research

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Purpose: Glioblastoma (GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier (BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM.Experimental Design: Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells overexpressing P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers (pAkt, p4EBP1, and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2, and GBM10 orthotopic models of GBM.Results: GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. GNE-317 was efficacious in the U87, GS2, and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively.Conclusions: These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.

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Section: Discussionmentioning

confidence: 99%

Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

Salphati

Heffron²,

Alicke³

et al. 2012

Clinical Cancer Research

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“…Agarwal and colleagues reported that ABCG2 has higher affinity for sorafenib than ABCB1 and play a dominant role in the efflux of sorafenib at the BBB in vivo study (25). Lagas and colleagues confirmed that brain efflux of sorafenib is more efficiently transported by ABCG2 with playing the dominant role in limiting its brain accumulation by murine Abcg2 (26). Among these publications, none of them shows that sorafenib is an inhibitor of the ABCG2 transporter.…”

Section: Discussionmentioning

confidence: 99%

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Wei

Zhao

et al. 2012

Molecular Cancer Therapeutics

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Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib, which has a dual-mode action by inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy.

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“…P-gp recognizes drugs with various structures and actions as its substrates (29), suggesting that it has an impact on the pharmacokinetics of a wide range of drugs, which include anticancer drugs, antiepileptic drugs, and immunosuppressive drugs, and that it may contribute to critical adverse events associated with these drugs (30,31). Indeed, several studies have indicated that bioavailability of paclitaxel (32), etoposide (ETP) (33), erlotinib (19), and sorafenib (34), all of which are anticancer drugs and P-gp substrates, are dramatically increased in mice with P-gp deficits after oral administration. Based on substantial evidence, P-gp is recognized as an extremely important factor in the regulation of the pharmacokinetics of drugs used in the clinic.…”

Section: Characterization Of P-gpmentioning

confidence: 99%

“…P-gp recognizes and transports a wide range of drugs, including a large number of anticancer drugs (29,34) and therefore influences their pharmacokinetics. Importantly, changes in the expression or functional activity of P-gp induced by anticancer drugs frequently causes high rates of multi-drug resistance in cancer cells (48) and also affects the disposition of various P-gp substrate drugs in normal tissues (1).…”

Section: Alteration In the Expression And Function Of P-gp Induced Bymentioning

confidence: 99%

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

et al. 2014

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Abstract. In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.Keywords: P-glycoprotein, anticancer drug, drug-drug interaction, opioid, cancer *Corresponding author. stoku@pharm.Kobegakuin.ac.jp Published online in J-STAGE on July 2, 2014 doi: 10.1254/jphs.14R01CRInvited article 243 Changes in P-gp by Anticancer Treatment targeted anticancer drugs acting on specific genes or their products has grown rapidly. In fact, combination treatment with molecularly targeted drugs and cytotoxic chemotherapy against cancers such as acute leukemia or lymphatic malignancy improved therapeutic outcome in comparison to conventional anticancer chemotherapy (8, 9). However, solid tumors often have greater inherent resistance and are less sensitive to anticancer drugs (10). Furthermore, chronic exposure to anticancer drugs frequently leads to multi-drug resistance where the therapeutic effects of these drugs on tumors is largely reduced (11). The development of resistance to anticancer chemotherapy remains one of the major obstacles in effective pharmacological therapy for cancer using current treatment strategies (12).Research revealing the role of drug transporters in cancer began with the discovery of P-glycoprotein (P-gp). In 1976, during research to elucidate the mechanism by which cancer cell lines acquire multi-drug resistance, Juliano et al. discovered that P-gp is over-expressed on the surface membranes of multi-drug resistant cancer cells (13). Subsequent studies have demonstrated that P-gp is present in cancer tissue (11,14), as well as in normal tissues such as small intestine, where it regulates drug absorption, and liver and kidney, where it modulates drug clearance (15). These results suggest that P-gp determines blood levels of its substrate drugs. Furthermore, P-gp is now considered to be an extremely important factor in the pharmacokinetics of drugs bec...

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Breast Cancer Resistance Protein and P-glycoprotein Limit Sorafenib Brain Accumulation

Cited by 168 publications

References 35 publications

Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Mechanisms of P-Glycoprotein Alteration During Anticancer Treatment: Role in the Pharmacokinetic and Pharmacological Effects of Various Substrate Drugs

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