Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance?

Abstract

Based on the concept presented in this review, TKI anticancer drugs are considered as compounds recognized by the cellular mechanisms handling xenobiotics. Accordingly, novel anticancer therapies should equally focus on the effectiveness of target inhibition and exploration of potential interactions of the designed molecules by membrane transporters. Thus, targeted hydrophobic small molecule compounds should also be screened to evade xenobiotic-sensing cellular mechanisms.

Tyrosine and aurora kinase inhibitors diminish transport function of multidrug resistance-associated protein (MRP) 4 and breast cancer resistance protein (BCRP)

“…In recent years, TKIs have been identified as inhibitors of several ATP-binding cassette (ABC) efflux transporters that are commonly upregulated in cancer cells including P-glycoprotein (multidrug resistance protein 1), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP) 1 [10][11][12][13][14][15][16][17][18]. ABC efflux transporters consist of a large family of membrane-spanning proteins involved in the active extrusion of substrates such as endogenous molecules, drugs, and drug metabolites from the cell through hydrolysis of ATP [19][20][21].…”

HER2 As Therapeutic Target for Overcoming ATP-Binding Cassette Transporter–Mediated Chemoresistance in Small Cell Lung Cancer

“…Therefore, additional effects apart from its direct inhibitory effect on RTKs are needed for TKIs to exert expected results in SCLC. Recently, it has been reported that many anticancer TKIs are substrates for ABC transporters and also act as inhibitors of them to increase intracellular accumulation of coexisting other substrates such as cytotoxic drugs (37)(38)(39). HER-TKIs (e.g., gefitinib, erlotinib, and lapatinib) have been shown to have potentials to restore sensitivity in chemoresistant cancer cells by inhibiting ABC transporter functions (7)(8)(9)14).…”

“…Lapatinib, like other TKIs, serves as a substrate of ABC transporters and is excreted from cells at lower concentrations. However, it functions as an inhibitor of ABC transporters at higher doses in turn (39). Therefore, in relapsed SCLC, lapatinib is expected to penetrate into metastatic brain tumors and reach the concentration enough to restore the chemosensitivity.…”

Hematopoietic Stem Cells in Chronic Myeloid Leukemia

“…CML stem cells have been shown to express the ATP dependent transporter cassette protein ABCG2, which could decrease the intracellular accumulation of Imatinib in CML LSC [103]. Thus, overexpression of ABC transporters gives protection to tumor cells from TKIs [114].…”