*3.2. The Involment of ABCG2 in Multidrug Resistance of Cancer*

Beyond its physiological roles, ABCG2 has been implicated in cancer multidrug resistance (recently reviewed in [7]). A large variety of chemotherapeutic agents has been identified as ABCG2 substrates. First, the anti-cancer drug mitoxantrone has been demonstrated to be exported by ABCG2, thus reducing its intracellular accumulation [4,71–73]. Interestingly, a kinetic analysis indicated that mitoxantrone is extruded by ABCG2 not from the cytosol but directly from the plasma membrane, where the drug accumulates [74]. Other anticancer drugs identified as ABCG2 substrates include flavopiridol [73,75], methotrexate [76], topotecan, and irinotecan [77,78]. In addition, several prominent tyrosine kinase inhibitors (TKIs) used in chemotherapies, such as gefitinib [79–81], imatinib [81–83], sunitinib [84], and nilotinib [83,85], were proven to be transported by ABCG2. The anti-cancer agents doxorubicin and daunorubicin have also been reported as ABCG2 substrates [4,72,75], but eventually it was revealed that these drugs are transported only by the R482G ABCG2 variant [3,86].

Expression of ABCG2 in tumors often correlates with poor prognosis, especially in hematopoietic malignancies, such as acute myeloid leukemia [87], but also in solid tumors, including diffuse large B-cell lymphoma [88]. However, clinical data are often conflicting like in the case of acute lymphocytic leukemia [89–91], or of breast carcinoma [92–94]. Several other studies demonstrated correlation between ABCG2 expression and response to chemotherapy, even to drugs, which are not ABCG2 substrates. These inconsistencies can originate from the modulatory effect of other drug resistance mechanisms, most evidently the presence of other MDR proteins. In addition, the methods employed to determine ABCG2 expression could be dubious, originating from the potential cross-reactivity of applied antibodies, or from the fact that mRNA levels of membrane proteins often do not correlate with the protein levels. The genetic background of patients could give an extra hue to these clinical studies as mutations and polymorphisms may alter the input of ABCG2 into the clinical outcome or the response to various drugs; therefore, proper stratification of patients is crucial for these analyses. In summary, the role of ABCG2 in tumors has been implicated, but its actual contribution to the clinical multidrug resistance is still unclear [6,7].
