Correlation between Multi-Drug Resistance-Associated Membrane Transport in Clonal Cancer Cells and the Cell Cycle Phase

Abstract

Multidrug resistance driven by ABC membrane transporters is one of the major reasons for treatment failure in human malignancy. Some limited evidence has previously been reported on the cell cycle dependence of ABC transporter expression. However, it has never been demonstrated that the functional activity of these transporters correlates with the cell cycle position. Here, we studied the rate of intrinsic ABC transport in different phases of the cell cycle in cultured MCF-7 breast cancer cells. The rate was characterized in terms of the efflux kinetics from cells loaded with an ABC transporter substrate. As averaging the kinetics over a cell population could lead to errors, we studied kinetics of ABC transport at the single-cell level. We found that the rate of ABC transport in MCF-7 cells could be described by Michaelis-Menten kinetics with two classical parameters, V max and K M . Each of these parameters showed similar unimodal distributions with different positions of maxima for cell subpopulations in the 2c and 4c states. Compared to the 2c cells, the 4c cells exhibited greater V max values, indicating a higher activity of transport. They also exhibited a greater V max / K M ratio, indicating a higher efficiency of transport. Our findings suggest that cell cycle-related modulation of MDR may need to be taken into account when designing chemotherapy regimens which include cytostatic agents.

Drug-loaded sickle cells programmed ex vivo for delayed hemolysis target hypoxic tumor microvessels and augment tumor drug delivery

“…Calcein is an established model drug and widely used in cell transport studies based on its physical properties [34-35]. Like many cancer therapeutics, it is a small molecule (molecular weight ~622) and relatively hydrophilic.…”

Upregulation of NEK2 is associated with drug resistance in ovarian cancer

“…In addition, the cell cycle is also involved in drug transportation in cancer. Multidrug resistance driven by ABC membrane transporters is one of the major reasons for treatment failure in human malignancies, and modulation of MDR by cell cycle-related factors has been observed in MCF-7 breast cancer cells (63). Microtubules are intracellular tubular structures found in all eukaryotic cells.…”

Multiscale Modelling of Cancer Progression and Treatment Control: The Role of Intracellular Heterogeneities in Chemotherapy Treatment

“…The results obtained from the multiscale model were in very good agreement with the previous experimental findings 6,33,34 and highlighted the role of intrinsic cell-cycle-driven drug resistance of slowly-cycling tumour subpopulation in the recurrence of the tumour after therapy. Future work will consider other factors that may induce drug resistance within a growing tumour mass such as variations in cell cycle control, anti-apoptotic proteins, multi-drug resistance through the activation of cellular pumps and increased metabolic activities 33,35,4 to study their role in tumour recurrence and analyse the various optimum delivery protocols for multiple chemotherapeutic drugs to achieve maximum therapeutic benefit.…”