Drug resistance: from bacteria to cancer

Abstract

The phenomenon of drug resistance has been a hindrance to therapeutic medicine since the late 1940s. There is a plethora of factors and mechanisms contributing to progression of drug resistance. From prokaryotes to complex cancers, drug resistance is a prevailing issue in clinical medicine. Although there are numerous factors causing and influencing the phenomenon of drug resistance, cellular transporters contribute to a noticeable majority. Efflux transporters form a huge family of proteins and are found in a vast number of species spanning from prokaryotes to complex organisms such as humans. During the last couple of decades, various approaches in analyses of biochemistry and pharmacology of transporters have led us to understand much more about drug resistance. In this review, we have discussed the structure, function, potential causes, and mechanisms of multidrug resistance in bacteria as well as cancers.

Keywords: ATP-binding cassette transporters; Chemotherapy; Drug resistance; Efflux pumps; Integrons.

Fig. 1

Drug resistance in bacteria. Target protein alteration. Certain modifications lead to impermeability of the cell membrane and thus decrease drug uptake. Target modification leads to a demoted drug binding. Integron Operon network. Integrons help insert a resistance gene at a pre-decided site downstream of a promoter (Example- Tn21). Anthropogenic activities. Release of toxic chemicals into the environment provides a selection and survival pressure which leads to variation and ultimately, evolution. Horizontal gene transfer. Transfer of genes from other species or from same species, but not parental cells is called HGT. Evolution of β-lactam antibiotic resistance genes is one of the results of HGT. Transposons. “Jumping genes” produces enzymes that aid in HGT. Mutation in porin genes. It can lead to decreased drug influx or increased drug efflux with the help of ion motive force, as compared to ATP hydrolysis by transporters

Fig. 2

Mechanisms by which drug resistance is conferred in cancer. (In clockwise manner starting with defective apoptotic pathway) (1) the apoptotic pathway (p53 pathway) might be defective, which leads to various downstream resistance mechanisms like upregulation of Nrf2 expression, MGM2 upregulation, increased cell proliferation, etc.; (2) drug resistance is seen when there is increased or defective immune system function where hypersensitivity is observed; (3) a plethora of epigenetic factors play roles in conferring drug resistance in cancer; (4) when the detox systems (ROS, homeostasis) are activated, there is a detox of the drug from the cancer cell; (5) drug delivery problems: too low concentration or higher molecule size than required; (6) drug alteration by intrinsic enzymes or other proteins; (7) transporters of the cell membrane exhibit increased drug efflux or decreased influx; (8) even if the drug enters the cell and affects the genetic machinery, there is an increased intrinsic DNA repair mechanisms; (9) drug resistance is also seen during increased metabolism in liver

Fig. 3

ABCB1 transporter (as a representative example of ABC superfamily of transporters). Normal functions of ABC transporters. (structure from RCSB PDB)

Fig. 4

Comparative representation P-gp and EmrE. a ABCB1 (P-gp) transporter, one of the most frequently overexpressed transporters in human cancers. ABCB1 confers resistance to anthracyclines, vinca alkaloids, epipodophyllotoxins, camptothecins, methotrexate, mitoxantrone, etc. b EmrE transporter of Escherichia coli, belonging to SMR family of drug efflux transporters. EmrE confers resistance to dodecyl dimethyl ammonium chloride (DDAC) or Ethidium bromide