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Anticancer Efficacy of Photodynamic Therapy with Lung Cancer-Targeted Nanoparticles
Published on: December 1, 2016
Enediyne-activated, EGFR-targeted human β-defensin 1 has therapeutic efficacy against non-small cell lung carcinoma
Wen-Juan Liu1, Kun-Li Zhu2, Jian Xu3
1Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, 250117, China.
Abstract:
Human β-defensins contain an oncolytic motif that binds to tumor cell membranes and mediate permeabilization, rapid induction of cytolysis, and apoptosis. Previous studies have indicated that a fragment of the mature human β-defensin-1 (HBD1) peptide (DF) has antitumor properties. While targeted drug treatments using fusion proteins have been shown to increase drug efficacy, this phenomenon has not been studied for this defensin. Thus, in this study, we designed and prepared a fusion protein containing this HBD1 fragment and an epidermal growth factor receptor (EGFR)-targeting oligopeptide (Ec) as well as lidamycin (LDM), an extremely potent cytotoxic antitumor antibiotic, which consists of an apoprotein (LDP) and a highly active enediyne (AE). The fusion protein (Ec-LDP-DF) and its enediyne-integrated fusion protein (Ec-LDP(AE)-DF) were then purified and used to treat lung carcinoma cells in culture as well as lung carcinoma xenograft mouse models. The multifunctional fusion protein Ec-LDP-DF was shown to effectively bind to EGFR-expressing tumor cells. Furthermore, the enediyne-energized Ec-LDP(AE)-DF analog exhibited extremely potent cytotoxicity in NSCLC cell lines and an IC50 less than 10-10 mol/L. Ec-LDP(AE)-DF also significantly inhibited the growth of human carcinoma A549 and H460 xenografts in athymic mice at well-tolerated doses. Treatment resulted in cell cycle arrest and apoptosis in a dose-dependent manner. EGF-stimulated EGFR phosphorylation was also abolished by Ec-LDP(AE)-DF. In summary, our understanding of the role of defensins in cancer development and progression is continually expanding, and Ec-LDP(AE)-DF is a promising cancer cell-targeting agent for NSCLC.
Insights
A novel fusion protein, Ec-LDP(AE)-DF, targets lung cancer cells by leveraging human beta-defensin-1 and an EGFR-targeting peptide. This potent agent induces apoptosis and inhibits tumor growth in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Human beta-defensins (HBDs) possess oncolytic properties, with a fragment of HBD1 (DF) showing antitumor effects.
- Targeted drug delivery using fusion proteins can enhance therapeutic efficacy, but this approach has not been explored for HBDs.
- Epidermal growth factor receptor (EGFR) is a validated target in non-small cell lung cancer (NSCLC).
Purpose of the Study:
- To design and synthesize a novel fusion protein incorporating an HBD1 fragment (DF), an EGFR-targeting oligopeptide (Ec), and lidamycin (LDM).
- To evaluate the efficacy and mechanism of action of the fusion protein, particularly its enediyne-integrated analog (Ec-LDP(AE)-DF), against NSCLC.
- To assess the potential of Ec-LDP(AE)-DF as a targeted therapeutic agent for NSCLC.
Main Methods:
- Construction and purification of fusion proteins: Ec-LDP-DF and Ec-LDP(AE)-DF.
- In vitro studies: Cytotoxicity assays on NSCLC cell lines, cell cycle analysis, apoptosis induction, and assessment of EGFR phosphorylation.
- In vivo studies: Treatment of human lung carcinoma xenografts in athymic mice to evaluate tumor growth inhibition and tolerability.
Main Results:
- The fusion protein Ec-LDP-DF effectively bound to EGFR-expressing tumor cells.
- The enediyne-energized fusion protein Ec-LDP(AE)-DF demonstrated extremely potent cytotoxicity against NSCLC cell lines (IC50 < 10-10 M).
- Ec-LDP(AE)-DF significantly inhibited xenograft tumor growth in mice at well-tolerated doses, inducing cell cycle arrest and apoptosis in a dose-dependent manner, and abolished EGF-stimulated EGFR phosphorylation.
Conclusions:
- The novel fusion protein Ec-LDP(AE)-DF is a highly potent and targeted therapeutic agent for NSCLC.
- This agent effectively inhibits tumor growth by inducing cell cycle arrest and apoptosis and by targeting EGFR signaling.
- Ec-LDP(AE)-DF represents a promising new strategy for NSCLC treatment, building upon the oncolytic potential of defensins.
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