Intensive fibrosarcoma-binding capability of the reconstituted analog and its antitumor activity

Abstract

Fibrosarcomas are highly aggressive malignant tumors. It is urgently needed to explore targeted drugs and modalities for more effective therapy. Matrix metalloproteinases (MMPs) play important roles in tumor progression and metastasis, while several MMPs are highly expressed in fibrosarcomas. In addition, tissue inhibitor of metalloproteinase 2 (TIMP2) displays specific interaction with MMPs. Therefore, TIMP2 may play an active role in the development of fibrosarcoma-targeting agents. In the current study, a TIMP2-based recombinant protein LT and its enediyne-integrated analog LTE were prepared; furthermore, the fibrosarcoma-binding intensity and antitumor activity were investigated. As shown, intense and selective binding capability of the protein LT to human fibrosarcoma specimens was confirmed by tissue microarray. Moreover, LTE, the enediyne-integrated analog of LT, exerted highly potent cytotoxicity to fibrosarcoma HT1080 cells, induced apoptosis, and caused G2/M arrest. LTE at 0.1 nM markedly suppressed the migration and invasion of HT1080 cells. LTE at tolerated dose of 0.6 mg/kg inhibited the tumor growth of fibrosarcoma xenograft in athymic mice. The study provides evidence that the TIMP2-based reconstituted analog LTE may be useful as a targeted drug for fibrosarcome therapy.

CDK11p110 plays a critical role in the tumorigenicity of esophageal squamous cell carcinoma cells and is a potential drug target

“…These results are congruent with those in osteosarcoma, liposarcoma, breast cancer and ovarian cancer, in which CDK11 p110 knockdown reduces cell or tumor growth [20][21][22][23]. As is well known, tumor cell migration is important not only for cancer development but also for cancer metastasis [28]. CDKs and their cyclin family are important for cell migration in several types of tumors.…”

“…The mice were injected subcutaneously in the right flank with untransfected EC109 cells, pLKO.1 vectorexpressing EC109 cells, shCDK11 p110 -1-expressing EC109 cells, shCDK11 p110 -2-expressing EC109 cells, pCDH-expressing EC109 cells, or pCDH-CDK11 p110 -expressing cells (2 × 10 6 cells in 100 μL PBS) to establish xenograft tumors (n = 7 per group). Tumor size was measured every 3-4 days, and tumor volume was calculated with the following formula: V (mm 3 ) = 0.5 × a× b 2 , where a and b represent the long and the perpendicular short diameters of the tumor, respectively [28]. The mice were sacrificed at 20 d after inoculation, and solid tumors were dissected, measured and photographed.…”

EGFR-targeting, β-defensin-tailored fusion protein exhibits high therapeutic efficacy against EGFR-expressed human carcinoma via mitochondria-mediated apoptosis

“…The binding specificity of the protein Ec-LDP-hBD1 to A431, A549, and H460 cells was evaluated with a fluorescence microscope. This assay was performed as previously reported [20,26]. The cells were then overlaid with mouse anti-His-Tag monoclonal antibodies.…”

Enediyne-activated, EGFR-targeted human β-defensin 1 has therapeutic efficacy against non-small cell lung carcinoma

“…In our laboratory, we have designed a variety of ligandbased, receptor-targeted drugs, including a EGFR-targeted, tuftsin-based fusion protein Ec-LDM-TF [15] as well as an a guided carrier-protein, LDP(AE)-TIMP2 [17,28] and Ec-LDP-TRAIL [19], which expresses an EGFR oligopeptide and tumor necrosis factor related apoptosisinducing ligand (TRAIL). This has allowed us to study the synergistic therapeutic effects of these fusion proteins.…”