Not only P-glycoprotein: amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins

The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment.Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoproteinor MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for exampletaxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of publishedpapers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematologicalmalignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo withanti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated,resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein overexpression,and multidrug resistance (MDR). Clearly however, additional mechanisms such as single nucleotidepolymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and ofother MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and thewealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vastknowledge from the bench to the bedside has proven to be unexpectedly difficult.Many studies show that upon repeated treatment schedules of cell cultures or tumors with taxenes and anthracyclinesas well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genesgenomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins maycontribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genescontained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed inmany cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. Thisreview describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possibleconnections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies toovercome cancer MDR.