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Substance P as a member of tachykinin family plays an important role in angiogenesis. Hemokinins (HKs) have been identified as new members of substance P-like peptides of tachykinin family. However, the effects of HKs on endothelial cells and angiogenesis have not been studied. For the first time, here we demonstrated that r/mHK-1, hHK-1 and hHK(4-11) dose-dependently stimulated the proliferation, migration, adhesion and tube formation of freshly isolated human umbilical vein endothelial cells (HUVECs), and further exhibited in vivo angiogenic effects in chick embryo chorioallantoic membrane model. The angiogenic effects of HKs were inhibited by the selective antagonist of neurokinin-1 rather than neurokinin-2 receptor. Mechanistically, HKs activated ERK1/2 phosphorylation, stimulated nitric oxide production, and upregulated the expression of endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) in HUVECs. Taken together, our data suggest that HKs emerge as pivotal endogenous regulators of angiogenesis and represent potential targets for the intervention of angiogenesis in different pathological conditions given their specific peripheral distribution.

Substance P, an 11-residue neuropeptide, can be rapidly internalized through specific interaction with the neurokinin-1 receptor. Therefore, we designed and synthesized the substance P targeted camptothecin (CPT) conjugates via a releasable disulfide carbonate linker. All the conjugates exhibited comparable or stronger cytotoxicity to cancer cells that highly over-express neurokinin-1 receptor than free CPT. More importantly, the selectivity of conjugates was significantly improved compared with CPT. Our results indicated that these conjugates can be promising candidates for new chemotherapeutic drugs. In addition, increasing CPT loading or attachment of CPT to the C-terminal hexapeptide of substance P are useful strategies to enhance the therapeutic efficacy of substance P targeted conjugates.