Reduced intracellular drug accumulation in drug-resistant leukemia cells is not solely due to MDR-mediated efflux but also to decreased uptake

• Published in: Frontiers in oncology 2014-10, Vol.4
• Main Authors: Angela Oliveira Pisco, Dean Andrew Jackson, Sui eHuang
• Format: Article
• Language: English
• Subjects: ABC transporters dependent drug resistance; Acute Myeloid Leukemia model; Cellular responses to anticancer drugs; Endocytosis-related multidrug resistance; Novel mechanism of multidrug resistance
• ISSN: 2234-943X
• DOI: 10.3389/fonc.2014.00306

Expression of ABC family transporter proteins that promote drug efflux from cancer cells is a widely observed mechanism of multi-drug resistance of cancer cells. Cell adaptation in long-term culture of HL60 leukemic cells in the presence of chemotherapy leads to induction and maintenance of the ABC transporters expression, preventing further accumulation of drugs. However, we found that decreased accumulation of drugs and fluorescent dyes was also contributed by a reduced uptake by the resistant cells. Confocal time-lapse microscopy and flow cytometry revealed that fluid-phase endocytosis was diminished in drug-resistant cells compared to drug-sensitive cells. Drug uptake was increased by insulin co-treatment when cells were grown in methylcellulose and monitored under the microscope, but not when cultured in suspension. We propose that multi-drug resistance is not solely achieved by enhanced efflux capacity but also by supressed intake of the drug offering an alternative target to overcome drug resistance or potentiate chemotherapy.