Abstract
The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention. The oncolytic peptide LTX-315 derived from bovine lactoferricin (LfcinB) was found to be highly effective against suspension cancer cells, but not adherent cancer cells. In this study, we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells. Thus, four hybrid peptides, NTP-212, NTP-217, NTP-223 and NTP-385, were synthesized. These hybrid peptides enhanced the anticancer activity of LTX-315 in a panel of adherent cancer cell lines by 2.4- to 37.5-fold. In model mice bearing B16-F10 melanoma xenografts, injection of NTP-385 (0.5 mg per mouse for 3 consecutive days) induced almost complete regression of melanoma, prolonged the median survival time and increased the overall survival. Notably, the administered dose of NTP-385 was only half the effective dose of LTX-315. We further revealed that unlike LTX-315, which targets the mitochondria, NTP-385 disrupted the nuclear membrane and accumulated in the nucleus, resulting in the transfer of a substantial amount of reactive oxygen species (ROS) from the cytoplasm to the nucleus through the fragmented nuclear membrane. This ultimately led to DNA double-strand break (DSB)-mediated intrinsic apoptosis. In conclusion, this study demonstrates that hybrid peptides obtained from the fusion of LTX-315 and rhodamine B enhance anti-adherent cancer cell activity by targeting the nucleus and triggering DNA DSB-mediated intrinsic apoptosis. This study also provides an advantageous reference for nucleus-targeting peptide modification.
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Acknowledgements
This project was supported by grants from the National Natural Science Foundation of China (81973299, 22177058, 82003647), the China Postdoctoral Science Foundation (2020T130332, 2019M652307), and the Qingdao postdoctoral application research project.
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HY designed research; HY performed research; YKQ designed oncolytic peptides; XTC, YNM and XYF synthesized peptides; HY and QNC performed MTT assay; HY and YKQ analyzed data; HY wrote the paper; SSD, YKQ and KWW prepared the paper.
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Yin, H., Chen, Xt., Chi, Qn. et al. The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus. Acta Pharmacol Sin 44, 201–210 (2023). https://doi.org/10.1038/s41401-022-00939-x
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DOI: https://doi.org/10.1038/s41401-022-00939-x
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