The Combination of Particle Irradiation With the Hedgehog Inhibitor GANT61 Differently Modulates the Radiosensitivity and Migration of Cancer Cells Compared to X-Ray Irradiation

Abstract

Due to the advantages of charged particles compared to conventional radiotherapy, a vast increase is noted in the use of particle therapy in the clinic. These advantages include an improved dose deposition and increased biological effectiveness. Metastasis is still an important cause of mortality in cancer patients and evidence has shown that conventional radiotherapy can increase the formation of metastasizing cells. An important pathway involved in the process of metastasis is the Hedgehog (Hh) signaling pathway. Recent studies have demonstrated that activation of the Hh pathway, in response to X-rays, can lead to radioresistance and increased migratory, and invasive capabilities of cancer cells. Here, we investigated the effect of X-rays, protons, and carbon ions on cell survival, migration, and Hh pathway gene expression in prostate cancer (PC3) and medulloblastoma (DAOY) cell lines. In addition, the potential modulation of cell survival and migration by the Hh pathway inhibitor GANT61 was investigated. We found that in both cell lines, carbon ions were more effective in decreasing cell survival and migration as well as inducing more significant alterations in the Hh pathway genes compared to X-rays or protons. In addition, we show here for the first time that the Hh inhibitor GANT61 is able to sensitize DAOY medulloblastoma cells to particle radiation (proton and carbon ion) but not to conventional X-rays. This important finding demonstrates that the results of combination treatment strategies with X-ray radiotherapy cannot be automatically extrapolated to particle therapy and should be investigated separately. In conclusion, combining GANT61 with particle radiation could offer a benefit for specific cancer types with regard to cancer cell survival.

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance

“…To the best of our knowledge only two studies looked into the effect of particles on the Hh pathway. Recently, we showed that carbon ions were more effective in inducing significant alterations in the Hh pathway than photons (102) and that carbon ions in combination with a Hh inhibitor was more efficient in decreasing migration of MCF-7 breast cancer cells than X-ray irradiation (170).…”

“…Therefore, particle therapy in combination with Hh inhibitors could offer an additional benefit for these patients due to the superior targeting. In a recent study, inhibition of Hh signaling radiosensitized medulloblastoma cells to both proton and carbon irradiation (102).…”

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

“…A recent study reports that GANT61 is able to sensitize DAOY cells to particle radiation (i.e. protons and carbon ions), but not to conventional X-rays [149] highlighting that the combination of GANT61 with particle radiation could offer a benefit for the treatment of specific cancer types.…”

Three discipline collaborative radiation therapy (3DCRT) special debate: The United States needs at least one carbon ion facility

“…For example, CIRT may limit HIF‐1a stabilization, MMP‐2 expression, and/or activation of the main epithelial–mesenchymal transition (EMT) signaling pathways that can trigger migration/invasion under normoxic and hypoxic conditions prevalent in radioresistant tumors relative to x rays . Compared to x rays or protons, carbon ions have also been reported to be more effective in decreasing cell survival and migration in prostate and pediatric medulloblastoma cells, as well as inducing more significant alteration in Hedgehog genes, another metastasis signaling pathway . Future biologically optimized treatment planning may be critical to the successful implementation of these advantages .…”