cytochalasin-e and Prostatic-Neoplasms

We have shown that the three human prostate xenograft tumors, i.e. the androgen-dependent CWR22 tumor, and the androgen-resistant CWR22R and CWR91 tumors, are comparable to patient tumors in their expression of prostate specific antigen, multidrug resistance p-glycoprotein, p53 and Bcl-2 and in their sensitivity to doxorubicin and paclitaxel. The present study used histocultures of these xenograft tumors to evaluate the antiproliferative and cytotoxic effects of several drugs (geldanamycin, cytochalasin E and thiacetazone), which have diverse action mechanisms and have shown activity against primary cultures of human prostate cancer cells. Suramin, a clinically active compound was included for comparison. Methods. The antiproliferative effect of 96 h drug treatment was measured by inhibition of DNA precursor incorporation, and the cytotoxic or cell kill effect was measured by in situ DNA end labeling of apoptotic and necrotic cells and by reduction of live cell density.. The rank order of molar potency was geldanamycin > cytochalasin E > suramin > or = thiacetazone. Thiacetazone produced antiproliferation only in CWR22 tumor and had no cytotoxicity, whereas the other three drugs produced both antiproliferation and cytotoxicity in all three tumors. Geldanamycin, but not cytochalasin E and suramin, showed greater antiproliferation and cytotoxicity in tumor cells compared to normal stromal cells. The two androgen-resistant tumors were 4 to >40-fold less sensitive than the androgen-dependent tumor to drug-induced antiproliferation but were about equally or 4 to >20-fold more sensitive to drug-induced cytotoxicity. The ratios of drug concentrations that produced 50% antiproliferation to the concentrations that produced 50% cytotoxicity ranged from <0.04 to 0.3 in CWR22 tumor, but ranged from 0.3 to 2.7 in CWR22R and CWR91 tumors, indicating a shift from antiproliferation as the predominant drug effect in the androgen-dependent tumor to cytotoxicity in the androgen-resistant tumors.. Our results indicate (a) differential drug effects in human prostate xenograft tumors with antiproliferation and cytotoxicity as the predominant drug effect in the androgen-dependent and androgen-resistant tumors, respectively, (b) that progression of tumors from androgen-dependent state to androgen-resistant state appears to be associated with a lower sensitivity to drug-induced antiproliferation and an equal or greater sensitivity to drug-induced cytotoxicity, and (c) that geldanamycin but not thiacetazone warrants further development.

Topics: Animals; Antineoplastic Agents; Benzoquinones; Cell Division; Culture Techniques; Cytochalasins; Humans; Lactams, Macrocyclic; Male; Mice; Mice, Nude; Prostatic Neoplasms; Quinones; Suramin; Thioacetazone; Transplantation, Heterologous

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