Arsenic trioxide prevents radiation-enhanced tumor invasiveness and inhibits matrix metalloproteinase-9 through downregulation of nuclear factor κB

Abstract

Arsenic trioxide (ATO) has been implicated as a promising anticancer agent by inhibiting cell growth and inducing apoptosis in certain types of cancer cells. This study explored the antimetastasis property of arsenic, drew potential link between arsenic use and radiotherapy, and uncovered the specific mechanisms underlying these remarkable responses. Using gelatin invasion assay and intravasation assay, we report the novel finding that low-dose ATO (1 lM) reduced the intrinsic migration ability of HeLa cells and significantly inhibited radiation-promoted tumor invasive potential of CaSki cells without inducing apoptotic cell death. Using the murine Lewis lung carcinoma model, the control animals and ATO treatment animals (1 mg/kg i.p., twice weekly) displayed similar in vivo growth kinetics, whereas the radiation (30 Gy in one fraction) and concurrent treatment groups showed considerable growth inhibition. Importantly, although concurrent treatment did not enhance the effectiveness of radiation therapy to the primary tumor, further examination of the lungs revealed that all animals succumbed to radiation-accelerated lung metastases could be effectively treated by combination of ATO and radiation. Radiationinduced matrix metalloproteinase-9 (MMP-9) expression was significantly inhibited by ATO using sequential analysis of the expression of MMPs in xenografts. Supporting this observation, ATO directly downregulates radiation-induced MMP-9 mRNA expression by inhibiting nuclear factor jB activity in human cervical cancer cells. In sum, concurrent arsenicradiation therapy not only achieves local tumor control but also inhibits distant metastasis. Experimental results of this study highlight a novel strategy in cancer treatment.

Arsenic trioxide reduces the invasive and metastatic properties of nasopharyngeal carcinoma cells in vitro

“…Essential steps include the degradation of extracellular matrix and basement membrane. The process involves multiple steps such as proliferation, adhesion and migration of tumor cells (11). In the present study, we found that As 2 O 3 inhibited the cell potential for proliferation, attachment, invasion, and migration.…”

“…Moreover, recent data indicated that As 2 O 3 can induce vascular shutdown and necrosis in esophageal carcinoma (10). In addition, As 2 O 3 has also been reported to inhibit radiation-induced cell invasion (11). Considering these data as a whole, it was reasonable to investigate whether As 2 O 3 is able to inhibit the invasive and metastatic activity of NPC cells.…”

Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-κB signal transduction pathway

“…In this study, NF-kB but not AP-1, modulated the radiation-induced MMP-9 activity in HepG2 cells on zymography. Wei et al (2005) also reported that NF-kB rather than AP-1 was involved in the radiation response of cervical cancer cell line Caski. We further demonstrated PI3K/Akt was involved in the radiation-induced NF-kB activity in HepG2 cells.…”

Notch-1 associates with IKKα and regulates IKK activity in cervical cancer cells

“…Inhibition of NF-kB sensitizes cervical cancer cells to cisplatin (Venkatraman et al, 2005). The cytotoxicity of arsenic trioxide (Woo et al, 2004;Wei et al, 2005) and celecoxib (Kim et al, 2004) on cervical cancer cells is mediated in part by NF-kB inhibition. Notch-1 is known to have complex, context-dependent cross talk with NF-kB, mediated by multiple cytoplasmic and nuclear pathways (Osipo et al, 2008).…”