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1.
Cancer Chemother Pharmacol ; 87(3): 425-436, 2021 03.
Article in English | MEDLINE | ID: mdl-33388950

ABSTRACT

PURPOSE: To investigate the antitumor efficacy of pingyangmycin (PYM) in combination with anti-PD-1 antibody and determine the capability of PYM to induce immunogenic cell death (ICD) in cancer cells. METHODS: The murine 4T1 breast cancer and B16 melanoma models were used for evaluation of therapeutic efficacy of the combination of PYM with anti-PD-1 antibody. The ELISA kits were used to quantify the ICD related ATP and HMGB1 levels. The Transwell assay was conducted to determine the chemotaxis ability of THP-1 cell in vitro. The flow cytometry was used to measure reactive oxygen species level and analyze the ratio of immune cell subsets. RESULTS: PYM induced ICD in murine 4T1 breast cancer and B16 melanoma cells and increased the release of nucleic acid fragments that may further promote the monocytic chemotaxis. In the 4T1 murine breast cancer model, PYM alone, anti-PD-1 antibody alone, and their combination suppressed tumor growth by 66.3%, 16.1% and 77.6%, respectively. PYM markedly enhanced the therapeutic efficacy of anti-PD-1 antibody against 4T1 breast cancer. The calculated CDI (coefficient of drug interaction) indicated synergistic effect. Evaluated by graphic analysis, the nucleated cells intensity in the femur bone marrow remained unchanged. Histopathological observations revealed no noticeable toxico-pathological changes in the lung and various organs, indicating that the PYM and anti-PD-1 antibody combination exerted enhanced efficacy at well-tolerated dosage level. By the combination treatment, a panel of immunological changes emerged. The ratio of CD3+ cells, NK cells and NKT cells increased and Tregs decreased in peripheral blood. The DCs increased in the spleen. Prominent changes occurred in tumor infiltrating lymphocytes. The ratio of CD8+ cells increased, while that of CD4+ cells decreased; however, the ratio of CD3+ cells remained unchanged, implying that certain immunological responses emerged in the tumor microenvironment. PYM alone could also increase CD8+ cells and reduce CD4+ cells in tumor infiltrating lymphocytes. CONCLUSIONS: The studies indicate that PYM, as an ICD inducer with mild myelosuppression effect, may enhance the therapeutic efficacy of anti-PD-1 antibody in association with tumor infiltrating CD8+ T cell augmentation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Mammary Neoplasms, Animal/drug therapy , Melanoma, Experimental/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , Antibodies/administration & dosage , Antibodies/immunology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bleomycin/administration & dosage , Bleomycin/analogs & derivatives , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Female , Lymphocytes, Tumor-Infiltrating/metabolism , Mammary Neoplasms, Animal/pathology , Melanoma, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Programmed Cell Death 1 Receptor/immunology , Tumor Microenvironment/immunology
2.
Drug Deliv ; 25(1): 102-111, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29250984

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.


Subject(s)
Antineoplastic Agents/pharmacology , Fibrosarcoma/drug therapy , A549 Cells , Animals , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Fibrosarcoma/metabolism , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Matrix Metalloproteinases/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Tissue Inhibitor of Metalloproteinase-2/metabolism
3.
Pharmacol Res ; 126: 66-76, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28392461

ABSTRACT

Overexpression of EGFR and MMP-2 plays an essential role in the initiation and progression of non-small-cell lung carcinoma (NSCLC). In this study, a novel format of EGFR/MMP-2 bi-targeted fusion protein Ec-LDP-TIMP2 and its enediyne-integrated analogue Ec-LDP(AE)-TIMP2 have been prepared by genetic engineering and molecular reconstitution. The Ec-LDP(AE)-TIMP2 comprises endogenous inhibitor of matrix metalloproteinase 2 (TIMP2), EGF-derived oligopeptide (Ec), lidamycin apoprotein (LDP), and the extremely potent cytotoxic enediyne (AE). By tissue microarray, Ec-LDP-TIMP2 showed high binding intensity and selectivity to human NSCLC specimens as compared with the matched non-cancerous tissues. By in vivo imaging, Ec-LDP-TIMP2 displayed prominent tumor-specific distribution in human NSCLC H460 xenograft. Particularly, Ec-LDP(AE)-TIMP2 inhibited tumor growth of H460 xenograft in athymic mice more striking. At doses of 0.2 and 0.4mg/kg, Ec-LDP(AE)-TIMP2 suppressed tumor growth by 74% and 89%, respectively. No histopathological changes were found in various organs of treated animals, suggesting that the effective dosage was tolerated. In summary, the ligand-based and enediyne-integrated fusion protein displaying extremely potent cytotoxicity might be highly effective for NSCLC therapy and useful as a carrier for drug delivery.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Matrix Metalloproteinase 2/metabolism , Recombinant Fusion Proteins/pharmacology , Tissue Inhibitor of Metalloproteinase-2/pharmacology , A549 Cells , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Female , Humans , Ligands , Lung Neoplasms/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Mice , Mice, Inbred BALB C , Mice, Nude , Oligopeptides/pharmacology , Xenograft Model Antitumor Assays/methods
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