Lung cancer is the leading cause of death in Taiwan cancer patients. The cancer cells are capable of spreading by metastasis and invasion. When tumors spread to distant parts of the body, it is difficult to treat by surgery. In this study, we discovered the novel anti-invasion drugs DMHMPC and DE-DMPC that can inhibit the metastasis and invasion of human lung cancer cell A549. From screening of a chemical library of 420 small molecule compounds using Boyden chamber and MTT assay, the compound DMHMPC and DE-DMPC showed the inhibitory activity toward the invasiveness but not proliferation in human lung cancer cell A549. The results of wound healing assay also showed that DMHMPC and DE-DMPC inhibited the motility of A549 in a dose dependent manner. Moreover, the results of growth curve assay and colony formation assay also showed that DMHMPC and DE-DMPC are not effect proliferation in A549. Together, these results suggested that DMHMPC and DE-DMPC could be the potential drugs to inhibit the invasion of cancer cells that may lead to the new avenue of the cancer prevention therapy.

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No / The development of therapeutics to treat cancer is conceptually more difficult than for nonlife-threatening diseases for several reasons, including its complex pathophysiological nature, the molecular individuality of each tumor, and the robustness and predictability of preclinical models toward determining efficacy and safety. A major limitation to development of a “blockbuster” therapeutic strategy is the infinite combination of cellular and molecular perturbations and associated heterogeneity of causative genetic factors driving disease progression. Although challenging, the diversity of drug targets, coupled with the lethality of the disease, has encouraged studies of a vast array of approaches and opportunities for disease treatment over the years.

Mannheimia haemolytica (M. haemolytica)-induced bovine respiratory disease causes millions of dollars in economic losses to Canadian cattle industry. Contemporary management strategies built around the use of antimicrobials are proving to be increasingly unavailing and lead to drug residues in meat which may contribute to the development of multi drug resistant bacteria. Many M. haemolytica vaccines are effective in stimulating antibody responses but studies of vaccina-tion in young calves and the cattle exposed to M. haemolytica (high-risk cattle) have shown poor vaccine efficacy. Antimicrobial peptides (AMPs) may help in the management of respiratory disease caused by M. haemolytica while minimizing the risk of drug residues in animal-derived food products. AMPs are positively charged molecules that can kill bacteria primarily through the electrostatic interactions with the anionic bacterial lipid bilayer. Since the primary target of AMPs is the bac-terial surface charge, which is evolutionarily conserved, the development of resistance towards AMPs seems less likely. These peptides hold potential to replace or reduce the use of antibiotics. Human β-Defensin 3 (HBD3) and Microcin J25 (MccJ25) are cationic peptides that have shown good activity against many Gram-negative bacteria. Five peptides, namely native HBD3, three synthetic HBD3 analogues (28 amino acid, 20AA, and 10AA), and MccJ25 were selected for microbicidal activity against M. haemolytica. Three C-terminal analogues of HBD3 with all cysteines replaced with valines were manually synthesized using solid phase peptide synthesis (SPPS). In all the three analogue, replacement of cysteine with valine rendered them linear and increased their antibacterial activity. Minimum Bactericidal concentration (MBC) assays were performed with the final inoculum size of 1-5x105 cells/ml, with the exception of the 10AA analogue which was incubated with 104 cells/ml final inoculum size. The antimicrobial assay showed that M. haemolytica was intermediately sensitive to HBD3, 28AA and 20AA analogue with an MBC of 50 µg/ml. MccJ25 had limited effect with an MBC greater than 100 µg/ml. The MBC value of 6.3 µg/ml achieved with the 10AA analogue is likely a result of lower final inoculum size. AMPs have several immunomodulatory functions, and these peptides can act as chemoattractant, induce cytokine release that in turn leads to chemotaxis of monocytes and neutrophils. Since neutrophils play an important role in the pathogenesis of BRD, the chemotactic effect of HBD3, 20AA and 28AA peptides on bovine neutrophils was studied using Boyden chamber. Peripheral blood neutrophils isolated from normal healthy cattle showed chemotaxis towards HBD3 and 20AA peptides (P<0.05) but not towards 28AA analogue. Co-incubation of neutrophils with any of the peptides did not affect their chemotaxis towards N-formyl-L-methionyl-L-leucyl-phenylalanine (fMLP). Based on these data, it can be concluded that HBD3 and its analogues showed antimicrobial ef-fects against M. haemolytica but MccJ25 had limited microbicidal activity against M. haemolytica. While HBD3 and 20AA analogue were chemotactic for bovine peripheral blood neutrophils, none of the peptides inhibited fMLP-induced migration of neutrophils. These peptides hold potential for further in vivo testing to develop them for use to manage M. haemolytica-induced respiratory disease in cattle.