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

Hao Yin1,2, Xi-tong Chen3, Qiao-na Chi4, Yan-nan Ma3, Xing-yan Fu3, Shan-shan Du4, Yun-kun Qi2,3, Ke-wei Wang1,2
1 Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, Qingdao University, #1 Ningde Road, Qingdao 266073, China
2 Institute of Innovative Drugs, Qingdao University, 38 Dengzhou Road, Qingdao 266021, China
3 Department of Medicinal Chemistry, School of Pharmacy, Qingdao University Medical College, Qingdao University, #1 Ningde Road, Qingdao 266073, China
4 College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
Correspondence to: Shan-shan Du:, Yun-kun Qi:, Ke-wei Wang:,
DOI: 10.1038/s41401-022-00939-x
Received: 20 April 2022
Accepted: 6 June 2022
Advance online: 6 July 2022


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.
Keywords: oncolytic peptides; LTX-315; rhodamine B; hybridization strategy; melanoma; ROS; DNA double-strand break; intrinsic apoptosis; nucleus-targeting peptides

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