Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer

Abstract

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.

What should be the future direction of development in the field of prostate cancer with lung metastasis?

“…In recent years, more systematic and precise screening and treatment have significantly improved the prognosis of PC up to a point[ 21 , 22 ]. However, effective treatment of PCLM still faces significant challenges and requires further exploration and breakthroughs[ 23 ]. Moreover, the number of PCLM patients is very large globally[ 1 , 2 , 4 ], which is further driving the exploration of and research into PCLM by scholars worldwide.…”

Parbendazole as a promising drug for inducing differentiation of acute myeloid leukemia cells with various subtypes

“…ABZ is a Food and Drug Administration (FDA)-approved broad-spectrum anthelmintic with low toxicity and is widely used in humans and animals 11 . Recently, ABZ has been reported to induce antitumor activities in various cancer types 12 – 14 . Moreover, several studies demonstrated that other benzimidazole anthelmintics (fenbendazole, flubendazole, and mebendazole) also induce anti-leukemic activities 15 – 17 .…”

Increased α2,3‐sialyl N‐glycosylated prostate‐specific membrane antigen (PSMA) in post‐DRE urine is associated with high grade group prostate cancer

“…On the other hand, 20% of the remaining patients with intermediate to high risk disease ultimately progress to aggressive metastatic forms of PCa which is incurable, and with a survival rate of 30%. [2][3][4][5][6] In clinical practice, currently two glycoproteins, prostate specific antigen (PSA) and prostate-specific membrane antigen (PSMA) are frequently used for the diagnosis of prostate cancer. PSA has limitations, and in 2012 the US Preventive Services Task Force recommended against the utilization PSA-based tests for screening the disease 7 based on low sensitivity and specificity as a biomarker.…”