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Treatment of Cancer Using Metal Coordinating Compounds that 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. Research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects, restricting their usefulness as therapeutics.

In an alternative approach to reducing the debilitating effects of MDR during cancer therapy, scientists at the NIH have identified a family of compounds whose activities are enhanced, rather than decreased, in MDR cancer cells. Particular embodiments of these "MDR-selective compounds" include certain metal coordinating compounds. Recent evidence suggests that these MDR-selective compounds can be used to kill cancer cells that overexpress ABC transporters or to re-sensitize multi-drug resistant cancer cells to chemotherapeutics. Furthermore, the effectiveness of these compositions in killing MDR cancer cells correlates directly with the level of ABC transporter expression. Importantly, MDR-selective compounds are not inhibitors of ABC transporters, thereby reducing the likelihood of undesirable side-effects during treatment. Thus, MDR-selective compounds represent a powerful strategy for treating multi-drug resistant cancers as a direct chemotherapeutic and as agents that can re-sensitize MDR cancer cells for treatment with additional chemotherapeutic agents.

Patent Abstract: 

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. Research has generally been directed to overcoming MDR by inhibiting the activity of ABC transporters. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects, restricting their usefulness as therapeutics.

In an alternative approach to reducing the debilitating effects of MDR during cancer therapy, scientists at the NIH have identified a family of compounds whose activities are enhanced, rather than decreased, in MDR cancer cells. Particular embodiments of these "MDR-selective compounds" include certain metal coordinating compounds. Recent evidence suggests that these MDR-selective compounds can be used to kill cancer cells that overexpress ABC transporters or to re-sensitize multi-drug resistant cancer cells to chemotherapeutics. Furthermore, the effectiveness of these compositions in killing MDR cancer cells correlates directly with the level of ABC transporter expression. Importantly, MDR-selective compounds are not inhibitors of ABC transporters, thereby reducing the likelihood of undesirable side-effects during treatment. Thus, MDR-selective compounds represent a powerful strategy for treating multi-drug resistant cancers as a direct chemotherapeutic and as agents that can re-sensitize MDR cancer cells for treatment with additional chemotherapeutic agents.

Benefits 
MDR- selective compounds capitalize on one of the most common drawbacks to cancer therapies (MDR) by using it as an advantage for treating cancer -The compositions do not inhibit the function of ABC transporters, reducing the chance of side-effects during treatment -The effects of MDR-selective compounds correlate with the level of ABC transporter expression, allowing healthy cells which do not express high levels of ABC transporters to better survive treatment
Inventors: 

Matthew Hall

Patent Number: 
61182,511 PCT Application No. PCTUS2010036348
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