A structured systems approach to problems of biological and biomedical relevance has helped to unravel the collective role of multiple drug transporters in multi-drug resistance.
Multi-drug resistance is the phenomenon by which different cells/microorganisms acquire resistance to a variety of drugs. It is seen in a broad range of settings, for instance in micro-organisms (resisting antimicrobial therapies) and cancer (resistance to anti-cancer therapies). It is an issue which significantly compromises drug treatment, leading to poorer outcomes and a marked increase in fatalities. Understanding the different factors underpinning multi-drug resistance is therefore of direct importance for designing effective therapies which circumvent this and lead to improved outcomes. A key ingredient in multi-drug resistance is the role of efflux transporters, which pump chemicals out of cells. In normal cell function, efflux transporters play a key role in cellular well-being, maintaining appropriate conditions inside the cell, by pumping out species which are either undesirable or in excess amount,
Cells employ a broad repertoire of transporters for pumping species/drugs (see schematic in Fig. 1(a)). As an example, three families of transporters are responsible for effluxing anti-cancer drugs. Individual transporters can pump out more than one drug, while more than one transporter can pump out a given drug. Furthermore the levels of one or more transporters is elevated in drug resistance. This leads to a basic question: what is the collective role of the totality of transporters? While understanding how a single transporter works is generally established, the collective functioning of multiple transporter types is not well understood. The challenge we are addressing is to understand the collective functioning of these transporters, their response to one or more drugs and their contribution to drug resistance, wherein one or more of these transporters may be present at elevated levels.
For this purpose, a systems framework was developed to examine the functioning of multiple transporters, their response to one or more drugs (either administered sequentially or simultaneously), and also examining the qualitatively different ways in which transporter levels may be increased (upregulated). It focusses on key sources of the associated complexity: the multiplicity of transporters and drug-transporter characteristics, the sequestration of transporters by drugs, and the effect of feedforward and feedback regulation of transporter levels. The systems investigation reveals the contribution of each of these features systematically. A systems approach is essential here as it allows us to probe the interactions between different separate elements on one hand, and their associated features on the other.
