New Use for an Old Drug: Inhibiting ABCG2 with Sorafenib

Abstract

Human ABCG2, a member of the ATP-binding cassette transporter superfamily, represents a promising target for sensitizing MDR in cancer chemotherapy. Although lots of ABCG2 inhibitors were identified, none of them has been tested clinically, maybe because of several problems such as toxicity or safety and pharmacokinetic uncertainty of compounds with novel chemical structures. One efficient solution is to rediscover new uses for existing drugs with known pharmacokinetics and safety profiles. Here, we found the new use for sorafenib, which has a dual-mode action by inducing ABCG2 degradation in lysosome in addition to inhibiting its function. Previously, we reported some novel dual-acting ABCG2 inhibitors that showed closer similarity to degradation-induced mechanism of action. On the basis of these ABCG2 inhibitors with diverse chemical structures, we developed a pharmacophore model for identifying the critical pharmacophore features necessary for dual-acting ABCG2 inhibitors. Sorafenib forms impressive alignment with the pharmacophore hypothesis, supporting the argument that sorafenib is a potential ABCG2 inhibitor. This is the first article that sorafenib may be a good candidate for chemosensitizing agent targeting ABCG2-mediated MDR. This study may facilitate the rediscovery of new functions of structurally diverse old drugs and provide a more effective and safe way of sensitizing MDR in cancer chemotherapy.

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

“…Indeed, the sorafenib-irinotecan combination was also more efficient than irinotecan alone in CRC cells in which ABCG2 was downregulated by shRNA. Sorafenib seems to have little effect on two other major ABC transporters (ABCB1 and ABCC1) involved in irinotecan efflux (20). On the other hand, irinotecan failure can also be related to activation of NF-kB and inhibition of the apoptotic cascade.…”

“…Sorafenib may, thus, decrease ABCG2 membrane expression by inhibiting these signaling pathways. Finally, Wei and colleagues proposed that sorafenib induces ABCG2 degradation via the lysosome (20). Taken together, these works suggest that sorafenib might inhibit both the function and the cell surface expression of ABCG2, ultimately leading to increased irinotecan cell concentration.…”

“…The molecular mechanism underlying the sorafenib effect on ABCG2 efflux function is still under investigation. In addition to ABCG2, sorafenib blocks the function of other ABC transporters, including ABCB1, ABCC2, and ABCC4 (20,31). Hu and colleagues showed that sorafenib inhibits the ATPase activity of ABCC2 by directly interacting with this ABC transporter (31).…”

“…In addition, it regulates the Raf-MEK-ERK pathway by inhibiting C-and B-Raf and, therefore, can affect tumor cell proliferation even in KRAS-mutated cancers (19). Moreover, sorafenib, like other TKIs, inhibits members of the ABC transporter superfamily, particularly ABCG2 (20).…”

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].…”