Eliminating Protein Pump Increases Sensitivity to Anti-Cancer Drugs

By eliminating an intracellular protein pump, cancer researchers have made mouse cells more sensitive to the taxane class of chemotherapeutic agents, which includes paclitaxel and docetaxel.

Investigators at the Fox Chase Cancer Center (Philadelphia, PA, USA) wanted to know whether eliminating the protein pump known as ATP-binding cassette transporter 10 (Abcc10) or multidrug resistance protein 7 (MRP7) would have any deleterious effects on cellular wellbeing. To this end, they genetically engineered a line of mice to lack the gene for Abcc10.

The Abcc10 "knockout" mice appeared normal and healthy in every respect, suggesting that Abcc10 was not essential for overall health and survival.

The investigators obtained mouse embryo fibroblasts derived from the knockout mice for a series of in vitro experiments to test their response to various anticancer drugs. Results published in the May 16, 2011 issue of the journal Cancer Research showed that the knockout fibroblasts were hypersensitive to docetaxel, paclitaxel, vincristine, and cytarabine (Ara-C) and exhibited increased cellular drug accumulation, relative to wild-type controls.

Living Abcc10 knockout mice were significantly more sensitive to the effects of the anticancer drugs than were normal controls. The knockout mice exhibited increased lethality associated with neutropenia and marked bone marrow toxicity as well as toxicity in spleen and thymus.

The development of drugs to block Abcc10 activity in cancer cells would seem to be the logical next step. However, first author Dr. Elizabeth A. Hopper-Borge, an assistant professor at Fox Chase Cancer Center, warned, "I would like to stress that we did this work in a mouse model. Our results so far suggest that this protein may be a clinically relevant target, but we need to do more studies to find out for sure."

Any application to human disease will require many more years of research.

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Fox Chase Cancer Center