The Breast Cancer Resistance Protein (BCRP), also known as ABCG2, is a member of the ATP-binding cassette (ABC) transporter family. It functions as an efflux pump, actively transporting a wide variety of structurally diverse compounds out of cells, a process powered by the hydrolysis of ATP. This crucial transporter is located in many parts of the body, including the intestinal lining, liver, kidneys, and the blood-brain barrier. By ejecting drugs and other xenobiotics from these tissues, BCRP significantly influences their absorption, distribution, and elimination, playing a protective role against harmful toxins. However, this protective mechanism can be a double-edged sword, especially in the context of drug therapy. When a drug inhibits BCRP, it can lead to increased systemic exposure of other drugs that are BCRP substrates, potentially causing dangerous drug-drug interactions (DDIs). Furthermore, overexpression of BCRP in cancer cells is a major contributor to multidrug resistance (MDR) by pumping chemotherapy drugs out before they can be effective. This has led to intense research into identifying and developing specific BCRP inhibitors to counteract MDR and improve therapeutic efficacy.
Classes of BCRP Inhibitors
Non-Specific BCRP Inhibitors
Many drugs can inhibit BCRP, often while also inhibiting other transporters like P-glycoprotein (P-gp), due to overlapping substrate specificities. These are often referred to as non-specific or broad-spectrum inhibitors. This includes a number of commonly used therapeutic agents across different classes:
- Tyrosine Kinase Inhibitors (TKIs): Several TKIs used for cancer therapy are potent inhibitors of BCRP. Examples include gefitinib, imatinib, nilotinib, and lapatinib.
- HIV Protease Inhibitors: This class of antiretrovirals, including ritonavir, saquinavir, and nelfinavir, exhibits inhibitory effects on BCRP.
- Antifungal Azoles: Medications like ketoconazole and itraconazole, used to treat fungal infections, also act as BCRP inhibitors.
- Immunosuppressants: Drugs such as cyclosporin A, tacrolimus, and sirolimus, which are used to prevent organ transplant rejection and treat autoimmune diseases, are known to inhibit BCRP.
- Proton Pump Inhibitors (PPIs): Some PPIs, like omeprazole and pantoprazole, are also recognized as BCRP inhibitors, though often less potent than other classes.
Specific and Experimental BCRP Inhibitors
Unlike the many non-specific inhibitors, highly selective BCRP inhibitors have been developed primarily for research purposes and to investigate their therapeutic potential. The first such compound identified was Fumitremorgin C (FTC), a mycotoxin from the fungus Aspergillus fumigatus. Because of its neurotoxicity, safer, more potent analogs have been developed, such as Ko143. Other candidates, like certain chromone derivatives and Tariquidar analogues, have been synthesized to achieve high potency and selectivity for BCRP over other ABC transporters.
Natural and Dietary BCRP Inhibitors
Interest in natural compounds that can modulate drug transporters has led to the discovery of several phytochemicals with BCRP inhibitory properties. These compounds are often found in common foods and spices:
- Curcumin: This compound, isolated from the spice turmeric, is a known inhibitor of BCRP and is studied for its potential to reverse multidrug resistance in cancer cells.
- Flavonoids: Many flavonoids, which are found in a wide variety of fruits and vegetables, can inhibit BCRP. Examples include genistein, chrysin, and biochanin A.
- Resveratrol: This antioxidant found in grapes and berries also exhibits BCRP inhibitory activity.
Clinical Significance of BCRP Inhibition
Drug-Drug Interactions (DDIs)
The most significant clinical consequence of BCRP inhibition is the potential for DDIs. Regulatory bodies like the FDA require new drugs to be tested for BCRP inhibition potential. A classic example involves the statin rosuvastatin, a BCRP substrate. When co-administered with a BCRP inhibitor, its absorption can increase significantly, raising the risk of adverse effects like myopathy. For example, studies have shown that BCRP inhibition can lead to a two-fold increase in rosuvastatin exposure. This is particularly relevant for individuals with certain BCRP genetic polymorphisms (like Q141K), which result in lower BCRP function and higher drug exposure even without a co-administered inhibitor.
Overcoming Multidrug Resistance in Cancer
BCRP is a major player in the development of MDR in various cancers, including acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). It actively pumps out chemotherapeutic agents such as mitoxantrone and topotecan, reducing their effectiveness. By inhibiting BCRP, the intracellular concentration of these drugs can be increased, potentially reversing resistance and improving treatment outcomes. While potent inhibitors exist, translating these findings to successful clinical therapies is challenging, and no specific BCRP inhibitor has been clinically approved for this purpose. The overlap with other transporters and potential toxicity are major hurdles.
Comparison of Specific vs. Non-Specific BCRP Inhibitors
| Feature | Non-Specific Inhibitors | Specific (Experimental) Inhibitors |
|---|---|---|
| Examples | Imatinib, Ritonavir, Ketoconazole | Fumitremorgin C, Ko143, Tariquidar analogues |
| Clinical Status | Many are approved drugs for other indications | Not clinically approved; used for research |
| Primary Use | Primarily prescribed for their main therapeutic effect; BCRP inhibition is a side effect leading to potential DDIs | Developed specifically for inhibiting BCRP to study its function or reverse drug resistance in labs |
| Inhibition Target | Often inhibit multiple ABC transporters (e.g., P-gp) and drug-metabolizing enzymes (e.g., CYP450) | Designed to target BCRP with high selectivity |
| Risk of DDI | High, especially with co-administration of BCRP substrates | Very low to none, as they are not clinically used; their research use focuses on targeted effects |
| Toxicity | Varies by drug class and patient; DDIs can cause dose-related toxicity | Often toxic at high concentrations (e.g., FTC); less toxic analogs have been developed for lab use |
Conclusion
Breast Cancer Resistance Protein (BCRP) is a fundamentally important efflux transporter that protects the body from xenobiotics but also poses significant challenges in pharmacology. Many commonly prescribed medications, including tyrosine kinase inhibitors, HIV protease inhibitors, and immunosuppressants, function as BCRP inhibitors, leading to potential drug-drug interactions that must be carefully managed. This inhibition can increase the bioavailability and toxicity of co-administered BCRP substrate drugs like rosuvastatin. Moreover, the role of BCRP in cancer multidrug resistance makes its inhibition a key target for improving chemotherapy efficacy, although no specific inhibitors have yet reached clinical use for this purpose. Future research is focused on developing more selective inhibitors with improved safety profiles. Understanding the interplay between BCRP and a wide range of pharmaceuticals is critical for modern medicine, ensuring both the safety and effectiveness of drug treatments. National Institutes of Health (NIH) - Targeting breast cancer resistance protein (BCRP/ABCG2) in cancer
