New matrix metalloproteinase inhibitor agent MMI-116 inhibits lymphogenous metastasis in orthotopically implanted SCID mouse model of the lung cancer

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Background: Recently many matrix metalloproteinase (MMP) inhibitors were isolated and characterized as anticancer drugs. MMI-166, an N-sulfonyl amino acid derivative, is the third-generation of MMP inhibitors which was designed to have a selective spectrum of MMP inhibition (MMP-2, MMP-9, and MMP-14). Many studies reported that MMP inhibitor inhibits hematogenous metastasis in animal models. However, there have been few studies on the effects of MMP inhibitor on lymphogenous metastasis. The purpose of the present study was to evaluate the effects of MMI-166 on both the growth of the implanted tumor and the lymph node metastasis of the mediastinum using orthotopically implanted SCID mouse model of Ma44-3 lung cancer cell line. Material and methods: We examined the anti-invasive effect of MMI-166, in 3 lung cancer cell lines (Ma10, Ma44-3, and Ma25) and fibrosarcoma cell line (HT-1080) using in vitro invasion assay. And we examined the anticancer effect of MMI-166 in vivo. MMI-166 (200μg/kg) or vehicle were administered orally from day 1 until day 14 after implantation in the orthotopically implanted SCID mouse model of Ma44-3 lung cancer cell line. Results: MMI-166 dose-dependently inhibited invasion of cancer cell lines (HT-1080, Ma10, and Ma44-3) with expressions of MMP-2 and/or MMP-9 through a basement membrane-like barrier in vitro. However, it was not able to inhibit invasion of cancer cell line (Ma25) without MMP-9 and MMP-2. In vivo, 200μg/kg of MMI-166 significantly suppressed the growth of Ma44-3 tumor implanted subcutaneously (tumor size on day 28, control: 4800±283 versus 200μg/kg MMI-166: 2301±565 mm³, p=0.011). However, MMI-166 did not significantly suppress the growth of Ma44-3 tumor implanted orthotopically ( tumor size, control: 736±559 versus 200μg/kg MMI-166: 589±358 ×10⁻³mm³, p=0.628) MMI-166 significantly inhibited the mediastinal lymph node metastasis in orthotopically implanted lung cancer model (weight of the mediastinum, control: 0.089±0.009 versus 200μg/kg MMI-166: 0.069±0.008 mg, p=0.005, the metastatic area, control: 93495±55747 versus 200μg/kg MMI-166: 22747±17478 pixels, p=0.045). Conclusion: These results showed that selective MMP inhibitor MMI-166 could inhibit lymph node metastasis, and that its anticancer effect was more sensitive to early-stage tumor than late-stage one.