Tamoxifen is a candidate first‐in‐class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells—Unrecognized players in tumorigenesis

• Published in: Cancer medicine (Malden, MA) Vol. 9; no. 9; pp. 3142 - 3152
• Main Authors: White‐Gilbertson, Shai, Lu, Ping, Jones, Christian M., Chiodini, Stephanie, Hurley, Deborah, Das, Arabinda, Delaney, Joe R., Norris, James S., Voelkel‐Johnson, Christina
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2020; John Wiley and Sons Inc; Wiley
• Subjects: acid ceramidase; Acid Ceramidase - antagonists & inhibitors; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Biomarkers, Tumor - metabolism; Brain cancer; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; cancer; Cancer Biology; Cancer therapies; Cell Cycle; Cell Division; Cell Proliferation; Ceramidase; Clinical trials; Drug dosages; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma; Histology; Humans; Medical diagnosis; Melanoma; Metastases; Middle Aged; Offspring; Original; PGCC offspring; Polyploidy; Prognosis; Prostate cancer; radiation therapy; recurrence; sphingolipid; Survival Rate; Tamoxifen; Tamoxifen - pharmacology; Tumor cells; Tumor Cells, Cultured; Tumorigenesis; North Carolina; United States > US; South Carolina; recurrence; polyploidy; sphingolipid; radiation therapy; PGCC offspring; cancer; tamoxifen; acid ceramidase
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.2960

Polyploid giant cancer cells (PGCC) represent a poorly understood, small subpopulation of tumor cells that are increasingly being recognized for their critical role in therapy resistance, metastasis, and cancer recurrence. PGCC have the potential to generate progeny through primitive or cleavage‐like division, which allows them to evade antimitotic insults. We recently demonstrated that the sphingolipid enzyme acid ceramidase (ASAH1) is required for this process. Since specific ASAH1 inhibitors are not clinically available, we investigated whether tamoxifen, which interferes with ASAH1 function via off‐target effects, has a potential clinical benefit independent of estrogen signaling. Our results show that tamoxifen inhibits generation of PGCC offspring in prostate cancer, glioblastoma, and melanoma cells. Analysis of two state‐level cancer registries revealed that tamoxifen improves survival outcomes for second, nonbreast cancers that develop in women with early stage breast cancer. Our results suggest that tamoxifen may have a clinical benefit in a variety of cancers that is independent of estrogen signaling and could be due to its inhibition of acid ceramidase. Thus the distinct application of tamoxifen as potentially a first‐in‐class therapeutic that inhibits the generation of PGCC offspring should be considered in future clinical trials. This study suggests that tamoxifen has an estrogen‐signaling independent clinical benefit in a variety of cancers that could be due to acid ceramidase inhibition. This would make tamoxifen a first‐in‐class therapeutic against formation of PGCC progeny.