latrunculin-b and Neoplasms

Clinical data shows that antitumor treatments are often ineffective if tumor cells have metastasized. To gain an effective antitumor therapeutic effect, in this report, the tumor cell was limited to the primary site and simultaneously ablated by chemotherapy. Considering the extremely complicated process of cancer metastasis, we seek to comprehensively suppress tumor metastases at both micro and macro levels, which closely link to migration and interact with each other. At the micro level, the motility of the tumor cell was decreased via accelerating mitochondria fusion. At the macro level, the unfavorable hypoxia environment was improved. A liposome-based multifunctional nanomedicine was designed by coloading latrunculin B (LAT-B), an inhibitor of actin polymerization, and doxorubicin (DOX) into the hydrophobic bilayers and aqueous cavity, respectively. Meanwhile, an oxygen reservoir named perfluoropentane (PFP) was encapsulated into the liposome core to fulfill synergistic treatment of metastatic tumors. In this paper, we demonstrated that the metastasis of the tumor cell could be effectively inhibited by LAT-B through promoting mitochondria fusion without affecting its function, making it as an encouraging candidate for effective anti-metastasis therapy. Meanwhile, we found that the combination of LAT-B and DOX shows a synergistic effect against tumors because the combined effect of these two drugs cover the entire cell proliferation process. In a word, this report presents a potential improvement in the treatment of metastatic cancer.

Topics: Actins; Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Doxorubicin; Drug Synergism; Humans; Liposomes; Mice, Nude; Neoplasms; Thiazolidines

Severe side effects often restrict clinical application of the widely used chemotherapeutic drug doxorubicin. In order to decrease required substance concentrations, new concepts for successful combination therapy are needed. Since doxorubicin causes DNA damage, combination with compounds that modulate DNA repair could be a promising strategy. Very recently, a role of nuclear actin for DNA damage repair has been proposed, making actin a potential target for cancer therapy in combination with DNA-damaging therapeutics. This is of special interest, since actin-binding compounds have not yet found their way into clinics. We find that low-dose combination treatment of doxorubicin with the actin polymerizer chondramide B (ChB) synergistically inhibits tumor growth in vivo. On the cellular level we demonstrate that actin binders inhibit distinctive double strand break (DSB) repair pathways. Actin manipulation impairs the recruitment of replication factor A (RPA) to the site of damage, a process crucial for homologous recombination. In addition, actin binders reduce autophosphorylation of DNA-dependent protein kinase (DNA-PK) during nonhomologous end joining. Our findings substantiate a direct involvement of actin in nuclear DSB repair pathways, and propose actin as a therapeutic target for combination therapy with DNA-damaging agents such as doxorubicin.

Topics: Actins; Animals; Antineoplastic Combined Chemotherapy Protocols; Bacterial Proteins; Bridged Bicyclo Compounds, Heterocyclic; Cell Death; Depsipeptides; DNA Damage; DNA End-Joining Repair; DNA Repair; DNA-Activated Protein Kinase; Doxorubicin; HeLa Cells; Humans; Ku Autoantigen; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasms; Phosphorylation; Recombination, Genetic; Replication Protein A; Thiazolidines; Transplantation, Heterologous

Cancer cells typically demonstrate altered morphology during the various stages of disease progression as well as metastasis. While much is known about how altered cell morphology in cancer is a result of genetic regulation, less is known about how changes in cell morphology affect cell function by influencing gene expression. In this study, we altered cell morphology in different types of cancer cells by disrupting the actin cytoskeleton or by modulating attachment and observed a rapid up-regulation of growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta (TGF-β) super-family. Strikingly, this up-regulation was sustained as long as the cell morphology remained altered but was reversed upon allowing cell morphology to return to its typical configuration. The potential significance of these findings was examined in vivo using a mouse model: a small number of cancer cells grown in diffusion chambers that altered morphology increased mouse serum GDF15. Taken together, we propose that during the process of metastasis, cancer cells experience changes in cell morphology, resulting in the increased production and secretion of GDF15 into the surrounding environment. This indicates a possible relationship between serum GDF15 levels and circulating tumor cells may exist. Further investigation into the exact nature of this relationship is warranted.

Topics: Actin Cytoskeleton; Animals; Bridged Bicyclo Compounds, Heterocyclic; Cell Adhesion; Cell Shape; Depsipeptides; Gene Expression Regulation, Neoplastic; Growth Differentiation Factor 15; HCT116 Cells; Humans; Mice, Nude; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; RNA, Messenger; Thiazolidines; Time Factors; Tumor Microenvironment; Up-Regulation

The wound healing assay in vitro is widely used for research and discovery in biology and medicine. This assay allows for observing the healing process in vitro in which the cells on the edges of the artificial wound migrate toward the wound area. The influence of different culture conditions can be measured by observing the change in the size of the wound area. For further investigation, more detailed measurements of the cell behaviors are required. In this paper, we present an application of automatic cell tracking in phase-contrast microscopy images to wound healing assay. The cell behaviors under three different culture conditions have been analyzed. Our cell tracking system can track individual cells during the healing process and provide detailed spatio-temporal measurements of cell behaviors. The application demonstrates the effectiveness of automatic cell tracking for quantitative and detailed analysis of the cell behaviors in wound healing assay in vitro.

Topics: Algorithms; Animals; Automation; Bridged Bicyclo Compounds, Heterocyclic; Cell Culture Techniques; Cell Line, Tumor; Cell Movement; Cell Tracking; Cells, Cultured; Culture Media; Equipment Design; Humans; Imaging, Three-Dimensional; Microscopy; Microscopy, Phase-Contrast; Mitosis; Neoplasms; Thiazolidines; Time Factors; Wound Healing