Breast cancer resistance protein (BCRP), scientifically known as ATP-binding cassette subfamily G member 2 (ABCG2), is a protein found on the surface of many cells. As a member of the ATP-binding cassette (ABC) transporter family, BCRP functions primarily as a cellular efflux pump. It uses energy derived from ATP to forcibly expel various substances, including foreign compounds (xenobiotics), out of the cell. This protein acts as a biological shield. BCRP inhibitors are compounds designed to interfere with this pump’s activity, thereby preventing the cell from removing its contents.
The Role of BCRP in Drug Transport and Resistance
The normal, physiological function of BCRP is fundamentally protective, serving as a detoxification mechanism in healthy tissues. The protein is strategically located at several biological barriers, acting as a gatekeeper to prevent the entry of potentially harmful molecules. High concentrations of BCRP are found in the apical membrane of the intestinal epithelium, where it limits the absorption of ingested drugs into the bloodstream.
BCRP is also highly expressed in the liver’s canalicular membrane, facilitating the excretion of compounds into bile for elimination. Furthermore, at the blood-brain barrier, BCRP strictly controls which substances can enter the sensitive brain tissue. While this protective role filters out natural toxins and environmental pollutants, the mechanism becomes detrimental in a clinical context when the “foreign substance” is a therapeutic drug.
The most problematic aspect of BCRP activity is its direct contribution to Multidrug Resistance (MDR) in cancer treatment. When BCRP is overexpressed on tumor cells, it actively pumps chemotherapy agents out before the drug reaches its cytotoxic target. This efflux causes the drug concentration inside the tumor cell to drop below the lethal level, rendering the treatment ineffective. BCRP exports numerous chemotherapeutics, including mitoxantrone, topotecan, and certain tyrosine kinase inhibitors, creating a major obstacle to successful cancer therapy.
Mechanisms of BCRP Inhibition
BCRP inhibitors function by physically or functionally interfering with the transporter’s ability to bind and expel its substrates. These compounds generally operate through two primary mechanisms: competitive or allosteric inhibition.
Competitive Inhibition
Competitive inhibition is the most straightforward method, where the inhibitor and the therapeutic drug vie for the same active binding site within the BCRP protein. If the inhibitor binds first, it physically blocks the drug from entering the pump and being transported out of the cell. The effectiveness of this mechanism is directly related to the concentration of the inhibitor, as high concentrations can effectively displace the drug-substrate.
Allosteric Inhibition
Allosteric inhibition does not involve a direct contest for the substrate binding site. Instead, the inhibitor binds to a separate location on the BCRP protein, known as an allosteric site. Binding to this distinct site causes a conformational change, twisting the protein’s structure into a non-functional shape. This structural deformation prevents the transporter from completing the energy-dependent process of expelling the drug.
Some inhibitors, such as Ko143, directly inhibit the BCRP’s ATPase activity. This process hydrolyzes ATP to release the energy needed for the transport cycle. By blocking this energy source, the pump is effectively disabled, representing a direct type of functional inhibition.
Clinical Applications of BCRP Inhibitors
The development of BCRP inhibitors is driven by two primary clinical goals: overcoming drug resistance in cancer and enhancing the absorption of beneficial medications.
Reversing Multidrug Resistance (MDR)
In oncology, the most studied application involves reversing Multidrug Resistance (MDR). Administering a BCRP inhibitor alongside a chemotherapy agent effectively “disarms” the efflux pump on the cancer cell surface. This co-administration forces tumor cells to retain higher, more toxic concentrations of the chemotherapy drug, restoring the cancer cell’s sensitivity to the treatment. Combining an inhibitor with drugs like topotecan or mitoxantrone aims to improve treatment efficacy and potentially reduce the required dosage. Although clinical trials have faced challenges, the rationale remains sound for improving patient outcomes in drug-resistant cancers.
Pharmacokinetic Enhancement
The second major application is pharmacokinetic enhancement, which focuses on improving the absorption and distribution of non-cancer drugs that are BCRP substrates. BCRP’s presence in the intestinal wall often limits the oral bioavailability of many medications, causing a large portion of the dose to be excreted before systemic circulation. Co-administering an inhibitor blocks this intestinal efflux, significantly increasing the amount of drug absorbed into the bloodstream.
This approach is particularly relevant for drugs intended to act in the central nervous system (CNS). The blood-brain barrier contains BCRP, which normally restricts drug entry into the brain. By temporarily inhibiting BCRP at this barrier, scientists aim to increase the drug’s penetration into the brain tissue, ensuring a higher concentration reaches the target area. For instance, the compound Elacridar has been studied for its potential to boost the bioavailability of various BCRP substrate drugs.
Classifications of BCRP Inhibitors
BCRP inhibitors are often classified based on their chemical structure, potency, and development history, mirroring other efflux pump modulators.
Early compounds, sometimes called first-generation inhibitors, often lacked specificity and inhibited multiple ABC transporters, such as both BCRP and P-glycoprotein (P-gp). These were primarily used as research tools to prove the concept of efflux pump modulation.
Second- and third-generation inhibitors were developed with improved potency and greater selectivity for BCRP. Elacridar (GF120918) is a potent, third-generation example that acts on both P-gp and BCRP and has advanced into clinical studies. Highly selective BCRP inhibitors, such as Ko143 and Fumitremorgin C (FTC), are frequently used in laboratory settings to isolate BCRP’s function.
Beyond synthetic molecules, many natural products also exhibit BCRP inhibitory activity. Certain plant-derived compounds, particularly flavonoids like gossypin, flavones, and flavonols, are recognized as avid inhibitors. These natural compounds suggest the potential for significant drug-food interactions, as dietary components can influence the function of this efflux transporter.