Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin.
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.
Hadaschik
Boris A
BA
The Prostate Centre at Vancouver General Hospital, Vancouver, BC, Canada.
Ettinger
Susan
S
Sowery
Richard D
RD
Zoubeidi
Amina
A
Andersen
Raymond J
RJ
Roberge
Michel
M
Gleave
Martin E
ME
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077143:Docetaxel; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C473896:HTI-286; D009842:Oligopeptides; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D043823:Taxoids; D000077143:Docetaxel; C467070:hemiasterlin