Tiopronin Specifically Kills and Re-sensitizes Multi-Drug Resistant Cells to Chemotherapy

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 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 have now discovered that the amino acid analog Tiopronin has the ability to kill multi-drug resistant cancer cells while leaving normal cells relatively unharmed. This suggests that Tiopronin can be developed as a therapeutic for multi-drug resistant cancers. Furthermore, Tiopronin re-sensitizes multi-drug resistant cells to chemotherapeutic agents over time. This may allow cyclical administration of chemotherapeutics without the development of permanent resistance to the agents, increasing the effectiveness of chemotherapy as a cancer treatment.

Importantly, Tiopronin is not an inhibitor of ABC transporter function because it kills multi-drug resistant cells without affecting the activity of ABC transporters. 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 Tiopronin. CRADA Opportunity: The National Cancer Institute, Multidrug Resistance Section, 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=2237

Daisy Fuentes Dania Ramirez Danica Patrick Daniella Alonso Danneel Harris