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1.
Mol Cancer Ther ; 15(12): 2916-2925, 2016 12.
Article in English | MEDLINE | ID: mdl-27638856

ABSTRACT

Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916-25. ©2016 AACR.


Subject(s)
Anilides/pharmacology , Carcinoma, Hepatocellular/metabolism , Focal Adhesion Kinase 1/antagonists & inhibitors , Liver Neoplasms/metabolism , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Anilides/chemistry , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Drug Synergism , Enzyme Activation/drug effects , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Phosphorylation , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , Pyridines/chemistry , Signal Transduction/drug effects , Tumor Burden/drug effects , Xenograft Model Antitumor Assays
2.
Support Care Cancer ; 23(4): 1043-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25277961

ABSTRACT

BACKGROUND: This is a single-center, prospective, observational study aiming to determine the effects of unidentified renal insufficiency (URI) on the safety and efficacy of chemotherapy for metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: mCRC patients with normal serum creatinine and who were treated with CapeOx as the first-line therapy were included. Creatinine clearance (CrCL) was estimated using the Cockcroft-Gault formula. URI was characterized by a CrCL of less than 60 ml/min. Logistic regression was used to assess the effects of URI on toxicities and response rates. Kaplan-Meier curve was used to evaluate the effect of URI on survival. RESULTS: A total of 143 patients were enrolled, of whom 34.9 % had URI. Compared with the control group, the URI group had longer toxicity durations and developed significantly more grade 1 to 2 toxicities after adjusting for age, gender, and body mass index. The toxicities include cytopenia (76 vs. 61 %, OR = 1.86, 95 % CI = 0.39-2.53, P < 0.001), diarrhea (34 vs. 29 %, OR = 3.76, 95 % CI = 0.95-6.53, P = 0.007), stomatitis (10 vs. 6 %, OR = 2.81, 95 % CI = 1.10-4.28, P = 0.002), and hand-foot syndrome (18 vs. 11 %, OR = 2.56, 95 % CI = 0.86-5.41, P = 0.045). The response rate and time to progression were significantly lower in the URI group than in the control group (4.5 vs. 5.5 months, HR = 1.57, 95 % CI = 1.09-2.25, P = 0.015), whereas the overall survival rates of the two groups were similar. CONCLUSION: In conclusion, URI can increase the toxicity and decrease the TTP of CapeOx-treated mCRC patients. Renal function screening via CrCL estimation is required for all mCRC patients before initial chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/complications , Colorectal Neoplasms/drug therapy , Renal Insufficiency/etiology , Adult , Aged , Colorectal Neoplasms/mortality , Disease Progression , Female , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Patient Safety , Prospective Studies , Renal Insufficiency/drug therapy , Renal Insufficiency/mortality , Survival Rate
3.
Article in Chinese | WPRIM (Western Pacific) | ID: wpr-255165

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the anticancer effect and its mechanism of SN-38 combined with sorafenib on hepatocellular cancer cell lines HepG-2 and BEL-7402.</p><p><b>METHODS</b>SRB colorimetry was employed to measure the viability of HepG-2 and BEL-7402 cells after the treatment of SN-38 with sorafenib. Propidium iodide flow cytometric assay and DAPI staining were used to evaluate the apoptosis of HCC cells. Western blotting was conducted to detect the expression level of apoptosis-related and DNA damage-related proteins.</p><p><b>RESULTS</b>SRB colorimetry showed the synergistic anticancer activities of SN-38 combined with sorafenib, with a combination index of <0.9. The apoptotic rates of HepG-2 cells in control, 60 nmol/L SN-38, 2.5μmol/L sorafenib and combination groups were 4.25%±2.45%, 28.95%±10.75%, 3.49%±2.49% and 53.19%±11.21%, respectively(P<0.05). Western blotting showed that the combination of these two drugs increased the enzymolysis of PARP, Caspase-8 and Caspase-3, and promoted the expression levels of p53, p21 and γ-H2AX significantly.</p><p><b>CONCLUSION</b>SN-38 and sorafenib have synergistic anticancer activity on hepatocellular carcinoma cells in vitro with the augmentation of apoptosis.</p>


Subject(s)
Humans , Apoptosis , Camptothecin , Pharmacology , Carcinoma, Hepatocellular , Pathology , Caspase 3 , Metabolism , Caspase 8 , Metabolism , Cell Line, Tumor , Cell Proliferation , Cyclin-Dependent Kinase Inhibitor p21 , Metabolism , Histones , Metabolism , Liver Neoplasms , Pathology , Niacinamide , Pharmacology , Phenylurea Compounds , Pharmacology , Poly(ADP-ribose) Polymerases , Metabolism , Tumor Suppressor Protein p53 , Metabolism
4.
Invest New Drugs ; 32(1): 75-86, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23903896

ABSTRACT

Utilization of antibodies to deliver highly potent cytotoxic agents to corresponding antigen-overexpressed tumor cells is a clinically validated therapeutic strategy. Ofatumumab (OFA, trade name Arzerra) is a fully human CD20-specific antibody that is active against CD20-positive B-cell lymphoma/chronic lymphocytic leukemia cells. In order to further enhance the anticancer effect of OFA, anti-CD20 OFA has been conjugated with highly cytotoxic monomethyl auristatin E (MMAE) through a cathepsin-B-cleavable valine-citrulline (vc) dipeptide linkage to form OFA-vcMMAE and the anti-tumor activity of OFA-vcMMAE against CD20-positive B lymphoma cells are then evaluated in vitro and in vivo. As a result, conjugation of OFA with MMAE has kept the initial effector functional activities of OFA such as binding affinity, complement-dependent cytotoxicity (CDC) as well as antibody-dependent cell-mediated cytotoxicity (ADCC). In addition, the conjugation of MMAE significantly improved the cytotoxic activity of OFA against CD20-positive cells (i.e., Raji, Daudi and WIL2-S cells) but not against CD20-negative K562 cells. On the other hand, OFA-vcMMAE was modulated from the CD20-positive cell surface and then entered the lysosomes by receptor-mediated endocytosis, underwent proteolytic degradation and released active drug MMAE to induce apoptotic cell death through a caspase-3-like protease-dependent pathway. Surprisingly, OFA-vcMMAE completely inhibited the growth of CD20-positive Daudi and Ramos lymphoma xenografts in vivo, and exhibited greater anti-tumor activity than unconjugated OFA, suggesting that the anti-tumor activity of anti-CD20 antibody can be enhanced by conjugation with MMAE. In the near future, this new approach might be used as a clinical treatment of CD20-positive B lymphoid malignancies.


Subject(s)
Aminobenzoates/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antigens, CD20/metabolism , Lymphoma, B-Cell/drug therapy , Molecular Targeted Therapy , Oligopeptides/therapeutic use , Aminobenzoates/chemistry , Aminobenzoates/pharmacology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibody-Dependent Cell Cytotoxicity/drug effects , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Death/drug effects , Cell Line, Tumor , Endocytosis/drug effects , Humans , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Lysosomes/metabolism , Male , Mice , Mice, SCID , Oligopeptides/chemistry , Oligopeptides/pharmacology , Trastuzumab , Xenograft Model Antitumor Assays
5.
Invest New Drugs ; 28(6): 800-11, 2010 Dec.
Article in English | MEDLINE | ID: mdl-19789842

ABSTRACT

Previous study demonstrated that MONCPT, a topoisomerase I inhibitor, exhibited potent anti-proliferation and anti-angiogenesis activity in vitro and in vivo. In this study, we report the efficacy of MONCPT against the development of melanoma metastasis by an intravenous injection of green fluorescent protein-transfected mice melanoma carcinoma (B16F10-GFP) cells in C57BL/6 mice. MONCPT (2.0, 5.0 and 12.5 mg/kg/2 days) markedly decreased B16F10-GFP pulmonary metastases by 12.8%, 53.1% and 76.3%, respectively; whereas higher doses of MONCPT (31.0 mg/kg/2 days) significantly inhibited the tumor growth of B16F10 xenograft model. In the in vitro experiment, MONCPT suppressed the B16F10-GFP cell invasion and migration without affecting cell survival. Further studies demonstrated that MONCPT decreased the secretion of matrix metalloproteinase (MMP)-9 and VEGF, and reduced the protein expression of HIF-1α as well as the phosphorylation level of ERK in B16F10-GFP cells. These in vivo and in vitro results indicate that MONCPT possesses both the potent antimetastatic ability and the tumor growth-inhibition activity, and the dual function promises MONCPT as a potential therapeutic agent for tumor metastasis and tumor growth of melanoma carcinoma.


Subject(s)
Camptothecin/analogs & derivatives , Disease Models, Animal , Melanoma/drug therapy , Melanoma/pathology , Neoplasm Metastasis/drug therapy , Animals , Camptothecin/pharmacology , Camptothecin/therapeutic use , Cell Adhesion/drug effects , Cell Hypoxia/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Separation , Drug Screening Assays, Antitumor , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Green Fluorescent Proteins/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Melanoma/enzymology , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness , Neoplasm Metastasis/pathology , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Transduction, Genetic , Vascular Endothelial Growth Factor A/metabolism
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