hti-286 and Prostatic-Neoplasms

Therapeutic resistance is the underlying cause for most cancer deaths and a major problem associated with treatment of metastatic prostate cancer. HTI-286, a fully synthetic analog of the natural tripeptide hemiasterlin, inhibits tubulin polymerization and circumvents transport-based resistance to taxanes. In our study, we evaluated its inhibitory effects on human prostate cancer growth in vitro and in different in vivo models. Androgen-dependent and androgen-independent prostate cancer cell lines including a docetaxel-refractory PC-3 subline (PC-3dR) were treated with HTI-286. Transcriptional profiling was carried out to screen for changes in gene expression induced by HTI-286 and compared to docetaxel. In vivo, nude mice with established PC-3 or PC-3dR xenografts were given HTI-286 intravenously. Additionally, mice bearing hormone-sensitive LNCaP tumors were treated with castration in combination with early or delayed HTI-286 therapy. In all cell lines tested, HTI-286 was a potent inhibitor of proliferation and induced marked increases in apoptosis. Despite similar transcriptomic changes regarding cell death and cell cycle regulating genes after exposure to HTI-286 or docetaxel, array analysis revealed distinct molecular signatures for both compounds. Invivo, HTI-286 significantly inhibited growth of PC-3 and LNCaP xenografts and retained potency in PC-3dR tumors. Simultaneous castration plus HTI-286 therapy was superior to sequential treatment in the LNCaP model. In conclusion, HTI-286 showed strong antitumor activity both in androgen-dependent and androgen- independent tumors and may be a promising agent in second- line treatment strategies for patients suffering from docetaxel- refractory prostate cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Cycle; Cell Proliferation; Docetaxel; Flow Cytometry; Gene Expression Profiling; Humans; Male; Mice; Mice, Nude; Neoplasms, Hormone-Dependent; Oligonucleotide Array Sequence Analysis; Oligopeptides; Prostatic Neoplasms; Radiation-Sensitizing Agents; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Taxoids; Tumor Cells, Cultured; Xenograft Model Antitumor Assays