The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus

• DOI: 10.1038/s41401-022-00939-x
• Publication Date: 2022-07-06T07:02:53Z
• Authors: Hao Yin; Xi-tong Chen; Qiao-na Chi; Yan-nan Ma; Xing-yan Fu; Shan-shan Du; Yun-kun Qi; Ke-wei Wang
• Keywords: Mice; 0303 health sciences; 03 medical and health sciences; Cell Line, Tumor; Humans; Animals; Apoptosis; DNA; Peptides; Melanoma; 3. Good health

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.