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. 2011;17(26):2793-802.
doi: 10.2174/138161211797440186.

Breast Cancer Resistance Protein and P-glycoprotein in Brain Cancer: Two Gatekeepers Team Up

Free PMC article

Breast Cancer Resistance Protein and P-glycoprotein in Brain Cancer: Two Gatekeepers Team Up

Sagar Agarwal et al. Curr Pharm Des. .
Free PMC article


Brain cancer is a devastating disease. Despite extensive research, treatment of brain tumors has been largely ineffective and the diagnosis of brain cancer remains uniformly fatal. Failure of brain cancer treatment may be in part due to limitations in drug delivery, influenced by the ABC drug efflux transporters P-gp and BCRP at the blood-brain and blood-tumor barriers, in brain tumor cells, as well as in brain tumor stem-like cells. P-gp and BCRP limit various anti-cancer drugs from entering the brain and tumor tissues, thus rendering chemotherapy ineffective. To overcome this obstacle, two strategies - targeting transporter regulation and direct transporter inhibition - have been proposed. In this review, we focus on these strategies. We first introduce the latest findings on signaling pathways that could potentially be targeted to down-regulate P-gp and BCRP expression and/or transport activity. We then highlight in detail the new paradigm of P-gp and BCRP working as a "cooperative team of gatekeepers" at the blood-brain barrier, discuss its ramifications for brain cancer therapy, and summarize the latest findings on dual P-gp/BCRP inhibitors. Finally, we provide a brief summary with conclusions and outline the perspectives for future research endeavors in this field.


Figure 1
Figure 1
Figure 1a. Transaxial PET images showing [11C] GF120918 in the brain of a (A) wild-type, (B) P-gp knockout, (C) Bcrp knockout and (D) P-gp/Bcrp knockout mouse. GF120918 is a substrate for and inhibits both P-gp and BCRP. The radioactivity level is low in the wild-type and BCRP knockout mouse, and increases slightly in the P-gp knockout mouse. The greatest increase in brain radioactivity is seen when both P-gp and BCRP are absent in the P-gp/Bcrp knockout mouse. Figure 1b shows the quantification of brain radioactivity in the four mouse types. Figures reproduced with permission from Kawamura et al., Mol Imaging Biol (2010), DOI: 10.1007/s11307-010-0313-1
Figure 2A
Figure 2A. Cooperation of P-gp and BCRP at the Blood-Brain Barrier
P-gp and BCRP work together at the BBB and restrict brain penetration of dual substrates. Absence of either P-gp or BCRP alone may not result in a significant increase in brain penetration of dual substrates. In BCRP knockout mice (where P-gp is present), P-gp alone is sufficient to prevent drugs from penetrating into the brain. Likewise, in P-gp knockout mice (where BCRP is present), BCRP also is sufficient to limit drug uptake into the brain. The greatest enhancement in brain penetration of dual substrates is always seen when both P-gp and BCRP are absent in the combined P-gp/BCRP knockout mice.
Figure 2B
Figure 2B. Impact of P-gp/BCRP Cooperation on Brain Distribution of Three Hypothetical Dual Substrates
Note: for both transporters it is assumed that protein expression correlates with transport capacity. i. For drugs with similar affinity for both P-gp and BCRP, P-gp is the dominant transporter due to higher P-gp protein expression levels at the BBB (higher transport capacity). Thus, P-gp-mediated drug efflux out of the brain is larger compared to BCRP-mediated efflux. As a result, the drug brain-to-plasma ratio is slightly increased in P-gp knockout mice, but unchanged in BCRP knockout mice. Absence of both P-gp and BCRP in P-gp/BCRP knockout mice results in drug brain levels that are significantly larger than the combined levels from the single transporter knockout mice. This phenomenon has been reported for drugs like dasatinib [14], gefitinib [12], topotecan [15], and lapatinib [16]. ii. For drugs with significantly higher affinity for BCRP than P-gp, BCRP is the dominant transporter in keeping these drugs out of the brain. The P-gp effect is only noticeable in BCRP knockout and combined P-gp/BCRP knockout mice. This has been observed for drugs like sorafenib [13] and dantrolene [90]. iii. For drugs with higher affinity for P-gp than BCRP, larger P-gp expression combined with high transporter affinity results in substantial P-gp-mediated efflux. In BCRP knockout mice, where P-gp is still present, drug brain-to-plasma ratio is unchanged. This has been reported for quinidine [90]. In all three scenarios the largest increase in drug brain-to-plasma ratio is seen when both P-gp and BCRP are absent at the BBB.
Figure 3
Figure 3. Comparison of BBB and Blood-Brain Tumor Barrier
A) Limited BBB permeability due to tight junctions and efflux transporters such as P-gp and BCRP. B) In the central core of brain tumors, the “blood-brain tumor barrier” is often disrupted and leaky resulting in increased barrier permeability for drugs.

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