jasplakinolide and Prostatic-Neoplasms

Jasplakinolide is a novel natural product anticancer agent which acts by inducing overpolymerization of actin. The aim of the current study was to explore the activity of jasplakinolide with hyperthermia and radiation.. The response of human PC-3 and DU-145 prostate carcinoma cells and DU-145 xenografts and the response of the Lewis lung carcinoma to jasplakinolide were studied.. Jasplakinolide was cytotoxic toward human prostate carcinoma cells, DU-145, PC-3 and LNCaP in culture, killing 1 log of cells with 0.8, 0.3 and 0.07 microM of drug in 24 h, respectively. The combination of jasplakinolide and hyperthermia resulted in primarily additive cell killing by the two modalities in the three prostate carcinoma lines. In combination with radiation, jasplakinolide produced some diminution in the shoulder of the survival curve of normally oxygenated PC-3 cells and was a radiation sensitizer of hypoxic DU-145 cells and hypoxic PC-3 cells. In vivo, jasplakinolide was an active antitumor agent against the Lewis lung carcinoma and the DU-145 prostate carcinoma xenograft. Jasplakinolide was a radiation sensitizer in the Lewis lung carcinoma. Jasplakinolide was also effective against the systemic Lewis lung carcinoma, decreasing lung metastases. Lung metastases were further decreased when jasplakinolide was administered along with radiation to the subcutaneous primary tumor. In the DU-145 tumor, the effects of jasplakinolide and fractionated radiation for 1 or 2 weeks appeared to be primarily additive.. Jasplakinolide is an interesting new anticancer agent for which further study both as an anticancer agent and in combined modality regimens is warranted.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Cell Division; Combined Modality Therapy; Depsipeptides; Humans; Hyperthermia, Induced; Male; Mice; Peptides, Cyclic; Prostatic Neoplasms; Tumor Cells, Cultured

Jasplakinolide is a member of a new class of antitumor agents targeting the actin cytoskeleton with activity against prostate cancer. Focal adhesion kinase (FAK) is an actin-associated mediator of mitogenic peptides. We hypothesized that the neuropeptide bombesin would activate FAR in prostate carcinoma, and that disruption of the actin network would block FAK activation and inhibit cell growth.. PC-3 human prostate carcinoma cells were exposed to 50-200 nM jasplakinolide (Jas) or cytochalasin E (CyE) in cytotoxicity experiments. FAK phosphorylation was measured in cells stimulated with 0.01-10 nM bombesin; separate cells were pretreated 6 hr with 50-500 nM Jas or CyE. Cell lysates and anti-FAK immunoprecipitates were subjected to SDS-PAGE, Western blotting, and detection with anti-actin or anti-phosphotyrosine. Depolymerized G-actin was separated from total actin by ultracentrifugation. Cytoskeletal changes were confirmed by fluorescence microscopy.. Jas (GI50 = 47 +/- 7 nM) and CyE (GI50 61 +/- 20 nM) potently inhibited PC-3 growth (P < 0.01 vs control). Bombesin rapidly stimulated tyrosine phosphorylation of FAK in a dose dependent manner. FAK phosphorylation was inhibited to near-basal levels (50% of bombesin stimulated) by 500 nM Jas (63%) and 500 nM CyE (61%).. Bombesin stimulated FAK in prostate carcinoma cells. Jasplakinolide, which induced over-polymerization of actin, and CyE, which depolymerizes actin, both inhibited bombesin-stimulated phosphorylation of FAK and inhibited PC-3 cell growth. Actin-disrupting agents block FAK signal transduction, which may be critical to their antitumor activity in prostate carcinoma.

Topics: Actins; Antineoplastic Agents; Bombesin; Cell Adhesion Molecules; Cell Line; Cytochalasins; Depsipeptides; Enzyme Activation; Enzyme Inhibitors; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Kinetics; Male; Peptides, Cyclic; Phosphorylation; Phosphotyrosine; Prostatic Neoplasms; Protein-Tyrosine Kinases; Tumor Cells, Cultured

Jasplakinolide, a cyclodepsipeptide produced by an Indo-Pacific sponge, Jaspis johnstoni, has been reported to inhibit the growth of breast cancer cells.. The effects of jasplakinolide on the proliferation of three human immortalized prostate carcinoma cell lines (PC-3, LNCaP, and TSU-Pr1) were studied. The growth-inhibitory effect of jasplakinolide on the PC-3 cell line was studied in detail to elucidate its mechanism of action.. Cell counts were used to study growth inhibition. A protein-based microplate assay was used to assess the time of exposure needed to cause persistent growth inhibition and to study the effects of jasplakinolide analogues. Metabolic changes were assessed by following the incorporation of radiolabeled precursors. The effects of jasplakinolide on the cytoskeleton were studied by fluorescent microscopy, using rhodamine phalloidin (RP) and antibodies to cytoskeletal components. Changes in RP binding were quantified by extracting bound fluorescent material from fixed cells and measuring the amount of fluorescence in a spectrofluorometer.. The growth of PC-3, LNCaP, and TSU-Pr1 cells was potently inhibited by exposure to jasplakinolide for 48 hours; doses of jasplakinolide that led to 50% growth inhibition were 65 nM for PC-3 cells, 41 nM for LNCaP cells, and 170 nM for TSU-Pr1 cells. In PC-3 cells, exposure to 160 nM for 48 hours led to total growth inhibition, which persisted for several days even after drug removal. Several jasplakinolide analogues also inhibited the growth of PC-3 cells, although analogues in which the rigidity of the macrolide ring was altered were ineffective. No early changes in the synthesis of DNA, RNA, or protein or in intracellular adenosine triphosphate levels were seen in the PC-3 cells after exposure to jasplakinolide. Growth inhibition by jasplakinolide was accompanied by striking morphologic changes. Exposure for several doublings led to multinucleated cells. Further investigation of these changes in the PC-3 cells revealed a dramatic and early disruption of the actin cytoskeleton and a statistically significant decrease in RP binding. The doses of jasplakinolide, the time of exposure, and the pattern of growth inhibition by structural analogues corresponded with the changes seen in actin distribution.. Jasplakinolide represents a novel marine natural product with potent in vitro antiproliferative activity against human prostate carcinoma cell lines, and it appears to target the actin cytoskeleton.. Jasplakinolide is a potential candidate for further preclinical development and a lead structure for a novel class of therapeutic agents that can disrupt the actin cytoskeleton in mammalian cells.

Topics: Actins; Antineoplastic Agents; Depsipeptides; Humans; Male; Peptides, Cyclic; Prostatic Neoplasms; Tumor Cells, Cultured