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

A novel compound, Imipramine Blue, enhances efficacy of chemotherapy in a single treatment against a rodent astrocytoma model in vivo by inhibiting cell invasion. 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. The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can “contain” GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase–mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB–mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.