Anti-Invasive Adjuvant Therapy with Imipramine Blue Enhances Chemotherapeutic Efficacy Against Glioma

Science Translational Medicine  28 Mar 2012:
Vol. 4, Issue 127, pp. 127ra36
DOI: 10.1126/scitranslmed.3003016

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Stopping the Invasion

A hallmark of brain cancer (glioma) is its diffuse nature, where the cancer cells migrate easily through the soft tissue, well away from the tumor site. By comparison, solid tumors, such as those found in breast, lung, and prostate, are more compact with defined margins. It is this cancerous invasion that makes gliomas so difficult to treat surgically and chemotherapeutically. Now, Munson and colleagues describe the synthesis and application of a new small molecule called Imipramine Blue (IB) to stop migrating cancer cells in their tracks. When combined with the anticancer drug doxorubicin (DXR), IB can help prolong the lives of diseased animals.

Munson et al. first tested the anti-invasive properties of IB in vitro in both human and rat glioma cell lines and in patient-derived neurospheres. Compared to untreated controls, IB was able to prevent cell outgrowth and invasion, without being toxic to the healthy cells. Similarly, IB packaged in liposomes for easy delivery (“nano-IB”) did not damage tissues or cause inflammation when injected into healthy rats—an important consideration for moving toward human testing. The authors then administered nano-IB to rats with an aggressive form of glioma (RT2) that shows key features of human brain cancer. Animals were treated with two doses of nano-IB and then killed for tumor analysis. Because IB inhibits invasion, the treated tumors were more compact than the controls. When the nano-IB was combined with a potent chemotherapeutic, liposomal DXR, 100% of the diseased rats were able to survive for 180 days, without any signs of regrowth by day 200. By comparison, only 33% of the animals treated with DXR lived that long. No untreated animals survived beyond 50 days.

Munson and colleagues also explored the mechanism behind IB’s anti-invasive properties, arriving at a molecular pathway that disrupts actin fiber formation; that is, cells are rendered completely unable to migrate without their intracellular actin machinery. By combining with a chemotherapeutic already used in the clinic, this invasion-stopping compound is poised for testing in more animal models, with the hopes of Food and Drug Administration approval.