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Published on: August 7, 2018
Hybrid peptide NTP-217 triggers ROS-mediated rapid necrosis in liver cancer cells by induction of mitochondrial
Hao Yin1, Xingyan Fu1, Hanyu Gao2
1School of Pharmacy, Qingdao University Medical College, Qingdao University, Qingdao, China.
Abstract:
Liver cancer is the third leading cause of cancer-associated mortality globally, and >830,000 patients with liver cancer undergoing treatment succumbed to the disease in 2020, which indicates the urgent need to develop a more effective anti-liver cancer drug. In our previous study, nucleus-targeting hybrid peptides obtained from the fusion of LTX-315 and the rhodamine B group possessed potent anti-adherent cancer cell activity. Hybrid peptides accumulated in the cell nucleus and damaged the nuclear membrane, resulting in the transfer of reactive oxygen species (ROS) from the cytoplasm to the nucleus and the induction of apoptosis. However, the source of the high concentration of ROS within the cytoplasm is unclear. Moreover, although our previous study demonstrated that hybrid peptides possessed potent anticancer activity against adherent cancer cells, their efficacy on liver cancer remained unexplored. The current study found that the hybrid peptide NTP-217 killed liver cancer cells after 4-h treatment with a half-maximal inhibitory concentration of 14.6-45.7 μM. NTP-217 could stably accumulate in the liver tumor tissue and markedly inhibited liver tumor growth in mice. Furthermore, NTP-217 destroyed mitochondria and induced the leakage of mitochondrial contents, resulting in the generation of a substantial quantity of ROS. Unlike the apoptosis induced by 24 h of treatment by NTP-217, 4 h of treatment caused ROS-mediated necrotic cell death. These findings suggested that short-time treatment with hybrid peptides could trigger ROS-mediated rapid necrosis in liver cancer cells, and provided a basis for the future development of hybrid peptides as anti-liver cancer agents.
Insights
A novel hybrid peptide, NTP-217, effectively targets liver cancer cells, inducing rapid necrosis via reactive oxygen species (ROS) and inhibiting tumor growth. This offers a promising new avenue for liver cancer drug development.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Liver cancer is a leading global cause of cancer mortality, necessitating novel therapeutic strategies.
- Previous research identified nucleus-targeting hybrid peptides with anti-adherent cancer cell activity, inducing apoptosis via nuclear membrane damage and reactive oxygen species (ROS).
- The source of cytoplasmic ROS and the efficacy of these hybrid peptides against liver cancer were previously unexplored.
Purpose of the Study:
- To investigate the efficacy of the hybrid peptide NTP-217 against liver cancer cells.
- To elucidate the mechanism of action of NTP-217 in liver cancer treatment.
- To evaluate the therapeutic potential of NTP-217 for liver cancer.
Main Methods:
- Treatment of liver cancer cells with NTP-217 and assessment of cell viability.
- In vivo studies involving NTP-217 administration to mice with liver tumors.
- Mitochondrial function analysis and ROS level quantification.
- Cell death pathway analysis (apoptosis vs. necrosis).
Main Results:
- NTP-217 demonstrated potent anti-liver cancer activity, inhibiting cell growth with a half-maximal inhibitory concentration (IC50) of 14.6–45.7 μM after 4-hour treatment.
- The peptide accumulated in liver tumor tissues and significantly suppressed tumor growth in vivo.
- NTP-217 induced mitochondrial damage and ROS generation, leading to ROS-mediated necrotic cell death within 4 hours, distinct from apoptosis induced by longer treatments.
Conclusions:
- Short-time treatment with NTP-217 triggers rapid, ROS-mediated necrosis in liver cancer cells.
- NTP-217 exhibits significant anti-liver cancer efficacy both in vitro and in vivo.
- These findings support the development of hybrid peptides like NTP-217 as potential anti-liver cancer agents.
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