Novel Compounds that Specifically Kill Multi-Drug Resistant Cancer Cells

One of the major hindrances to successful cancer chemotherapy is the development of multi-drug resistance (MDR) in cancer cells. MDR is frequently caused by the increased expression or activity of ABC transporter proteins in response to the toxic agents used in chemotherapy. The increased expression or activity of the ABC transporter proteins causes the toxic agents to be removed from cells before they can act to kill the cell. As a result, research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters, thus causing the chemotherapeutic agents to remain in the cell long enough to exert their effects. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects due to the inhibition of ABC transporter function in normal cells, thereby restricting their usefulness as therapeutics.

Investigators at the NIH previously identified novel compounds with the ability to kill multi-drug resistant cancer cells while leaving normal cells relatively unharmed. These “MDR-selective compounds” were not inhibitors of ABC transporters because they killed multi0drug resistant cells without affecting the activity of ABC transporters. Furthermore, their activity was dependent directly on the level of expression of ABC transporters, thus increasing their selectivity for diseased cells. As a result, the undesirable side-effects that have prevented the use of inhibitors of ABC transporters as therapeutics should not affect the therapeutic application of the MDR-selective compounds.

The inventors have now generated third generation MDR-selective compounds with further improved solubility, selectivity and killing activity toward MDR cells. The new MDR-selective compounds selectively kill MDR cancer cells, and their efficacy correlates directly with the level of ABC transporter expression. This suggests that the third generation MDR-selective compounds represent a powerful strategy for treating MDR cancers. CRADA Opportunity: The Center for Cancer Research, Laboratory of Cell Biology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize this technology. Please contact John Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.Click here to view the NCI collaborative opportunity announcement.

Source: http://www.ott.nih.gov/Technologies/abstractDetails.aspx?RefNo=2192

Amanda Bynes Amanda Detmer Amanda Marcum Amanda Peet Amanda Righetti