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In the present study, we evaluated whether C-type natriuretic peptide (CNP) alone or combined with cisplatin (CDDP) can inhibit cell proliferation and invasion of B16F10 cells. The cell viability assay, Western blot, qPCR, and Boyden chamber assays were performed to assess cell proliferation, inflammation, and invasion of B16F10 cells. Dose-dependent inhibition of cell proliferation was noticed in CNP alone treated cells, with 50% inhibition seen at 10μM of CNP. A significant reduction in cell proliferation markers (Cyclin D1 and PCNA, p<0.05), inflammation markers (NF-κB, TNF-α, and COX-2, p<0.05), and invasion markers (MMP-2/-9, p<0.05) were observed in B16F10 cells treated with CNP. A more prominent cell proliferation inhibition was noticed in a combination of CNP+CDDP treatment. Furthermore, when there was an increase in the concentration of CNP (5μM to 10μM) along with CDDP (2μM), strongly decreases the cell proliferation, inflammatory markers (p<0.01) and invasion (35% and 17%, p<0.01) of B16F10 cells as compared with CNP/CDDP alone treatment cells, respectively. The present study results demonstrate that CNP alone treatment potentially suppresses the cell proliferation, inflammation, and invasion of the B16F10 cells. Furthermore, to improve the inhibitory effects on cell proliferation of anti-cancer agents, we found that the combination of CNP and a non-cytotoxic concentration of CDDP increases the anti-proliferation and anti-invasion activity. Our results suggest that CNP possesses a unique role in inhibitory effects on cell proliferation and metastatic levels of B16F10 cells. Further, the CNP and CDDP combination may be helpful in the therapeutic purpose of cancer.