Dequalinium blocks macrophage-induced metastasis following local radiation

// Michael Timaner 1, * , Rotem Bril 1, * , Orit Kaidar-Person 2 , Chen Rachman-Tzemah 1 , Dror Alishekevitz 1 , Ruslana Kotsofruk 1 , Valeria Miller 1 , Alexander Nevelsky 2 , Shahar Daniel 2 , Ziv Raviv 1 , Susan A. Rotenberg 3 , Yuval Shaked 1 1 Department of Cell biology and cancer science, Rappaport Faculty of Medicine, Technion, Haifa, Israel 2 Department of Radio-Oncology, Rambam Health Care Campus, Haifa, Israel 3 Department of Chemistry and Biochemistry, Queens College of the City University of New York, Flushing, NY, USA * These authors have contributed equally to this work Correspondence to: Yuval Shaked, e-mail: yshaked@tx.technion.ac.il Keywords: radiotherapy, macrophages, colon cancer, tumor microenvironment Received: March 25, 2015      Accepted: July 24, 2015      Published: August 06, 2015 ABSTRACT A major therapeutic obstacle in clinical oncology is intrinsic or acquired resistance to therapy, leading to subsequent relapse. We have previously shown that systemic administration of different cytotoxic drugs can induce a host response that contributes to tumor angiogenesis, regrowth and metastasis. Here we characterize the host response to a single dose of local radiation, and its contribution to tumor progression and metastasis. We show that plasma from locally irradiated mice increases the migratory and invasive properties of colon carcinoma cells. Furthermore, locally irradiated mice intravenously injected with CT26 colon carcinoma cells succumb to pulmonary metastasis earlier than their respective controls. Consequently, orthotopically implanted SW480 human colon carcinoma cells in mice that underwent radiation, exhibited increased metastasis to the lungs and liver compared to their control tumors. The irradiated tumors exhibited an increase in the colonization of macrophages compared to their respective controls; and macrophage depletion in irradiated tumor-bearing mice reduces the number of metastatic lesions. Finally, the anti-tumor agent, dequalinium-14, in addition to its anti-tumor effect, reduces macrophage motility, inhibits macrophage infiltration of irradiated tumors and reduces the extent of metastasis in locally irradiated mice. Overall, this study demonstrates the adverse effects of local radiation on the host that result in macrophage-induced metastasis.