Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine kinase inhibitors (TKIs) are promising new agents for specific inhibition of malignant cell growth and metastasis formation. Because most of the TKIs have to reach an intracellular target, specific membrane transporters may significantly modulate their effectiveness. In addition, the hydrophobic TKIs may interact with so-called multidrug transporters and thus alter the cellular distribution of unrelated pharmacological agents. In the present work, we show that certain TKIs, already in the clinical phase of drug development, directly interact with the ABCG2 multidrug transporter protein with a high affinity. We found that in several in vitro assay systems, STI-571 (Gleevec; imatinib mesylate), ZD1839 (Iressa; gefitinib), and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (EKI-785) interacted with ABCG2 at submicromolar concentrations, whereas other multidrug transporters, human multidrug resistance protein (P-glycoprotein, ABCB1) and human multidrug resistance protein 1 (ABCC1), showed much lower reactivity toward these agents. Low concentrations of the TKIs examined selectively modulated ABCG2-ATPase activity, inhibited ABCG2-dependent active drug extrusion, and significantly affected drug resistance patterns in cells expressing ABCG2. Our results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the clinical treatment of cancer patients. These data also raise the possibility that an extrusion of TKIs by multidrug transporters, e.g., ABCG2, may be involved in tumor cell TKI resistance.
 ...
PMID:High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. 1515 41

Tyrosine kinase inhibitors (TKIs) are a new class of highly-selective and molecularly targeted anticancer agents. Most of these newly developed TKIs are hydrophobic, thus allowing them to rapidly penetrate the cell membrane to reach their specific intracellular targets. However, their therapeutic potential could be significantly hindered by the overexpression of certain ATP binding cassette (ABC) membrane transporters, which extrude hydrophobic drugs and result in cellular resistance to TKIs by tumor cells. Moreover, it has been recently demonstrated that some TKIs could upregulate ABC transporters in tumor cells, thereby effectively reducing their intracellular accumulation and antitumor efficacy. On the other hand, other TKIs were found to interact with ABC transporters and reverse multi-drug resistance (MDR) of tumor cells. In this review, the interaction of several TKIs, currently in clinical use or being developed in clinical trials, with the MDR-related ABC transporters, in particular ABCB1, ABCC1 and ABCG2, will be discussed.
 ...
PMID:Interaction of tyrosine kinase inhibitors with the MDR- related ABC transporter proteins. 2081 4

Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporter such as ABCB1, ABCC1, ABCG2 limited successful cancer chemotherapy. Unfortunately, no commercial available MDR modulator approved by FDA was used in clinic. Tyrosine kinase inhibitors (TKIs) have been administrated to fight against cancer for decades. Almost TKI was used alone in clinic. However, drug combinations acting synergistically to kill cancer cells have become increasingly important in cancer chemotherapy as an approach for the recurrent resistant disease. Here, we summarize the effect of TKIs on enhancing the efficacy of conventional chemotherapeutic drug in ABC transporter-mediated MDR cancer cells, which encourage to further discuss and study in clinic.
 ...
PMID:Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells. 2945 46