Nicaraven reduces cancer metastasis to irradiated lungs by decreasing CCL8 and macrophage recruitment

Abstract

Radiotherapy for cancer patients damages normal tissues, thereby inducing an inflammatory response and promoting cancer metastasis. We investigated whether nicaraven, a compound with radioprotective and anti-inflammatory properties, could attenuate radiation-induced cancer metastasis to the lungs of mice. Nicaraven and amifostine, another commercial radioprotective agent, had limited effects on both the radiosensitivity of Lewis lung carcinoma cells in vitro and radiation-induced tumor growth inhibition in vivo. Using experimental and spontaneous metastasis models, we confirmed that thorax irradiation with 5 Gy X-rays dramatically increased the number of tumors in the lungs. Interestingly, the number of tumors in the lungs was significantly reduced by administering nicaraven but not by administering amifostine daily after radiation exposure. Furthermore, nicaraven administration effectively inhibited CCL8 expression and macrophage recruitment in the lungs 1 day after thorax irradiation. Our data suggest that nicaraven attenuates radiation-induced lung metastasis, likely by regulating the inflammatory response after radiation exposure.

Nicaraven Attenuates Postoperative Systemic Inflammatory Responses-Induced Tumor Metastasis

“…N IR with nicaraven administration cytokines/chemokines. 3,14 Therefore, we also tested whether nicaraven could attenuate postoperative SIR-induced tumor metastasis. As expected, many cytokines/chemokines were obviously increased in plasma of mice at 6 h after intestinal I/R injury, suggesting systemic inflammatory responses.…”

“…The timing and dosage of nicaraven administration were based on our past studies, but it was required to be further validated by additional experiments. 3,10,15 Increasing evidences have shown the relationship between inflammatory cytokines/cells and tumor metastasis in recent years. It has been reported that TNF-a enhances tumor invasiveness and alters the tumor microenvironment to promote metastasis.…”

“…1,2 It has recently been demonstrated that excessive production of cytokines/chemokines and the increased infiltration of inflammatory cells promote cancer metastasis to the lungs. 3 Beyond bacterial/viral infections, systemic inflammatory responses (SIR) can be widely caused by various pathological conditions, such as major surgery and other noninfectious severe damages/injuries of tissues/organs. Because surgical resection is one of the most effective treatments for cancer and some cancer patients also may suffer to surgical procedures due to other severe diseases, it is critical to investigate whether extensive surgical procedures promote cancer metastasis.…”

“…[4][5][6] We have recently further demonstrated that nicaraven attenuates the enhanced tumor metastasis to lungs after thoracic radiation exposure, which likely associates with the decreased cytokines/chemokines in plasma and the infiltration of inflammatory cells in lungs. 3 Taking the antiinflammatory role of nicaraven into consideration, it is quite possible that nicaraven also inhibits the SIR-induced cancer metastasis after major surgery.…”

Low Molecular Weight Fucoidan Prevents Radiation-Induced Fibrosis and Secondary Tumors in a Zebrafish Model

“…New potential radioprotectants also have been developed including amifostine analog S-[2-(3-methylaminopropyl) aminoethyl] phosphorothioate acid, thiolamine compounds with thioglycoside-protecting groups, covalent conjugates of thioamines and antioxidant vitamins, and selenazolidine prodrugs [ 12 ]. Among them, amifostine exhibits potential preventing radiation-induced cell death and mutagenesis and has entered phase I clinical study [ 13 ], nicaraven prevents radiation-induced lung cancer metastasis [ 14 ], zoledronate prevents radiation-induced bone loss [ 15 ], and tangeretin inhibits irradiation-induced lung metastasis [ 16 ]. Nevertheless, none of them have studied the protective effect against irradiation-induced liver fibrosis.…”