The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy

Abstract

A major difficulty in the treatment of cancers is the poor response of many tumors to pharmacological regimens. This situation can be accounted for by the existence of a variety of complex mechanisms of chemoresistance (MOCs), leading to reduced intracellular concentrations of active agents, changes in the molecular targets of the drugs, enhanced repair of drug-induced modifications in macromolecules, stimulation of anti-apoptotic mechanisms, and inhibition of pro-apoptotic mechanisms. The present review focuses on alterations in the expression and appearance of the genetic variants that affect the genes involved in reducing the amount of active agents inside tumor cells. These alterations can occur through two mechanisms: either by lowering uptake or enhancing efflux (so-called MOC-1a and MOC-1b, respectively), or by decreasing the activation of prodrugs or enhancing inactivation of active agents through their biotransformation (MOC-2). The development of chemosensitizers that are useful in implementing the pharmacological manipulation of these processes constitutes a challenge to modern pharmacology. Nevertheless, the important physiological roles of the most relevant genes involved in MOC-1a, MOC-1b, and MOC-2 make it difficult to prevent the side effects of chemosensitizers. A more attainable goal in this area of pharmacological enquiry is the identification of proteomic profiles that will permit oncologists to accurately predict a lack of response to a given regimen, which would be useful for adapting treatment to the personal situation of each patient.

Epigenetic events involved in organic cation transporter 1‐dependent impaired response of hepatocellular carcinoma to sorafenib

“…Several types of MOC account for this limitation (Marin et al, 2010). Two of them (MOC-1 and MOC-2) participate in the reduction in intracellular concentrations of active drugs (Marin et al, 2014). It should be considered that to carry out their pharmacological action, TKIs must interact with the catalytic site of TK receptors, which are located intracellularly.…”

Identifying genes that mediate anthracyline toxicity in immune cells

“…A number of post-translational modifications also occur in APP; APP is extensively glycosylated in extra- and intracellular domains and is phosphorylated at several residues in its cytoplasmic domain, which interacts with multiple proteins (Muresan and Ladescu Muresan, 2015 ). The intracellular concentrations of active drugs may be affected by these modifications in general (Marin et al, 2014 ); however, the effect of drugs, particularly idarubicin, on these processes in APP warrants further investigation.…”

Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma

“…Drug efflux is a major molecular mechanism thought to affect drug resistance in patients with HCC. Increased drug efflux can decrease the accumulation of anticancer drugs ( 5 ). Multidrug resistance proteins (MRPs) are members of the ATP-binding cassette (ABC) transporter superfamily and are involved in drug efflux ( 6 ), contributing to the drug resistance observed in patients with HCC ( 5 ).…”