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Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis.

Jiang WG, Lu XA, Shang BY, Fu Y, Zhang SH, Zhou D, Li L, Li Y, Luo Y, Zhen YS - BMC Cancer (2013)

Bottom Line: ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability.Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice.The ES-based fusion protein therapy provides some fundamental information for further drug development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P, R, China. yluo@tsinghua.edu.cn.

ABSTRACT

Background: Endostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It also shows antiangiogenesis and antitumor activities in several animal models. Endostatin specifically targets tumor vasculature to block tumor growth. Lidamycin (LDM), which consists of an active enediyne chromophore (AE) and a non-covalently bound apo-protein (LDP), is a member of chromoprotein family of antitumor antibiotics with extremely potent cytotoxicity to cancer cells. Therefore, we reasoned that endostatin-lidamycin (ES-LDM) fusion proteins upon energizing with enediyne chromophore may obtain the combined capability targeting tumor vasculature and tumor cell by respective ES and LDM moiety.

Methods: In this study, we designed and obtained two new endostatin-based fusion proteins, endostatin-LDP (ES-LDP) and LDP-endostatin (LDP-ES). In vitro, the antiangiogenic effect of fusion proteins was determined by the wound healing assay and tube formation assay and the cytotoxicity of their enediyne-energized analogs was evaluated by CCK-8 assay. Tissue microarray was used to analyze the binding affinity of LDP, ES or ES-LDP with specimens of human lung tissue and lung tumor. The in vivo efficacy of the fusion proteins was evaluated with human lung carcinoma PG-BE1 xenograft and the experimental metastasis model of 4T1-luc breast cancer.

Results: ES-LDP and LDP-ES disrupted the formation of endothelial tube structures and inhibited endothelial cell migration. Evidently, ES-LDP accumulated in the tumor and suppressed tumor growth and metastasis. ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability. Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice.

Conclusions: The ES-based fusion protein therapy provides some fundamental information for further drug development. Targeting both tumor vasculature and tumor cells by endostatin-based fusion proteins and their enediyne-energized analogs probably provides a promising modality in cancer therapy.

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Optical imaging in living animal using DyLight 680-labeled ES-LDP or LDP-ES. Color scale represents photons/s/cm2/steradian, the red dot-cycle indicated the tumor location.
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Figure 4: Optical imaging in living animal using DyLight 680-labeled ES-LDP or LDP-ES. Color scale represents photons/s/cm2/steradian, the red dot-cycle indicated the tumor location.

Mentions: As expected, ES-LDP protein accumulated into the tumor area and reached the highest level within 1 h after injection and then gradually cleared from the tumor area during the following 3 hours (Figure 4, Upper). Surprisingly, DyLight 680-labeled LDP-ES showed little accumulation in PG-BE1 tumor, but a random distribution in the whole body followed by a normal clearance process (Figure 4, Lower). However, this observation is consistent with our previous result obtained with LDP [25], which indicates that fusion LDP to the N-terminus of ES does not improve the targeting of LDP.


Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis.

Jiang WG, Lu XA, Shang BY, Fu Y, Zhang SH, Zhou D, Li L, Li Y, Luo Y, Zhen YS - BMC Cancer (2013)

Optical imaging in living animal using DyLight 680-labeled ES-LDP or LDP-ES. Color scale represents photons/s/cm2/steradian, the red dot-cycle indicated the tumor location.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016579&req=5

Figure 4: Optical imaging in living animal using DyLight 680-labeled ES-LDP or LDP-ES. Color scale represents photons/s/cm2/steradian, the red dot-cycle indicated the tumor location.
Mentions: As expected, ES-LDP protein accumulated into the tumor area and reached the highest level within 1 h after injection and then gradually cleared from the tumor area during the following 3 hours (Figure 4, Upper). Surprisingly, DyLight 680-labeled LDP-ES showed little accumulation in PG-BE1 tumor, but a random distribution in the whole body followed by a normal clearance process (Figure 4, Lower). However, this observation is consistent with our previous result obtained with LDP [25], which indicates that fusion LDP to the N-terminus of ES does not improve the targeting of LDP.

Bottom Line: ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability.Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice.The ES-based fusion protein therapy provides some fundamental information for further drug development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P, R, China. yluo@tsinghua.edu.cn.

ABSTRACT

Background: Endostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It also shows antiangiogenesis and antitumor activities in several animal models. Endostatin specifically targets tumor vasculature to block tumor growth. Lidamycin (LDM), which consists of an active enediyne chromophore (AE) and a non-covalently bound apo-protein (LDP), is a member of chromoprotein family of antitumor antibiotics with extremely potent cytotoxicity to cancer cells. Therefore, we reasoned that endostatin-lidamycin (ES-LDM) fusion proteins upon energizing with enediyne chromophore may obtain the combined capability targeting tumor vasculature and tumor cell by respective ES and LDM moiety.

Methods: In this study, we designed and obtained two new endostatin-based fusion proteins, endostatin-LDP (ES-LDP) and LDP-endostatin (LDP-ES). In vitro, the antiangiogenic effect of fusion proteins was determined by the wound healing assay and tube formation assay and the cytotoxicity of their enediyne-energized analogs was evaluated by CCK-8 assay. Tissue microarray was used to analyze the binding affinity of LDP, ES or ES-LDP with specimens of human lung tissue and lung tumor. The in vivo efficacy of the fusion proteins was evaluated with human lung carcinoma PG-BE1 xenograft and the experimental metastasis model of 4T1-luc breast cancer.

Results: ES-LDP and LDP-ES disrupted the formation of endothelial tube structures and inhibited endothelial cell migration. Evidently, ES-LDP accumulated in the tumor and suppressed tumor growth and metastasis. ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability. Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice.

Conclusions: The ES-based fusion protein therapy provides some fundamental information for further drug development. Targeting both tumor vasculature and tumor cells by endostatin-based fusion proteins and their enediyne-energized analogs probably provides a promising modality in cancer therapy.

Show MeSH
Related in: MedlinePlus