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-glycoprotein
or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example
taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published
papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological
malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with
anti-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 nucleotide
polymorphisms (SNPs) and epigenetic modifications have shown a role in the overexpression of ABCB1 and of
other MDR efflux pumps. However, notwithstanding the design of 4 generations of ABCB1 inhibitors and the
wealth of information on the biochemistry and substrate specificity of ABC transporters, translation of this vast
knowledge 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 anthracyclines
as well as other chemotherapeutic drugs, amplification, and/or overexpression of a series of genes
genomically surrounding the ABCB1 locus, is observed. Consequently, altered levels of other proteins may
contribute to the establishment of the MDR phenotype, and lead to poor clinical outcome. Thus, the genes
contained in this ABCB1 amplicon including ABCB4, SRI, DBF4, TMEM243, and RUNDC3B are overexpressed in
many cancers, and especially in MDR tumors, while TP53TG1 and DMTF1 are bona fide tumor suppressors. This
review describes the role of these genes in cancer and especially in the acquisition of MDR, elucidates possible
connections in transcriptional regulation (co-amplification/repression) of genes belonging to the same ABCB1
amplicon region, and delineates their novel emerging contributions to tumor biology and possible strategies to
overcome cancer MDR