Abstract While prostate cancer is among the most treatable disease when the tumor stays confined to the prostate, the prognosis is generally poor for patients whose cancer metastasizes to distant organs. Current chemotherapy is relatively limited for metastatic prostate cancer, and thus there is a demand for more efficacious treatments. Here, we described a novel screen of a library containing approved drugs, for compounds that selectively target metastatic prostate cancer cells. We identified that benzimidazoles, widely used as anti-parasitic agents, exhibit preferential toxicity in two paired of human prostate cancer cells with different metastatic potential and in an aggressive rat prostate adenocarcinoma model but showed minimal cell kill on normal prostate epithelial cells. As these drugs are highly water-insoluble, we improved the systemic bioavailability in mice using a micelle preparation. Benzimidazoles significantly extend the lifespan of tumor metastases-bearing mice (% increased life span, ILS 40-60 range), without severe toxicity to the host. Notably, these anti-tumor effects are comparable if not more effective than paclitaxel (%ILS 30). The selective cytotoxicity to the metastatic cells is mediated partly by inhibition of the microtubulin polymerization, leading to mitotic arrest and subsequently cell death. These cytotoxic effects are also observed in cancer cells with paclitaxel or multi-drug resistance, both in vitro and in vivo. The benzimidazoles may possess significant anti-tumor effects and a good safety profile that are desired in the long term treatment of men with late-stage prostate cancer and failed both hormone-deprivation and taxane-based therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1551.
In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients’ prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo . The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases – two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.
