Tamoxifen is a candidate first-in-class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells-Unrecognized players in tumorigenesis.,Cancer Medicine

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Tamoxifen is a candidate first-in-class inhibitor of acid ceramidase that reduces amitotic division in polyploid giant cancer cells-Unrecognized players in tumorigenesis.
Cancer Medicine ( IF 2.9 ) Pub Date : 2020-03-05 , DOI: 10.1002/cam4.2960
Shai White-Gilbertson ₁ , Ping Lu ₁ , Christian M Jones ₂ , Stephanie Chiodini ₃ , Deborah Hurley ₃ , Arabinda Das ₄ , Joe R Delaney ₂ , James S Norris ₁ , Christina Voelkel-Johnson _{1,

2}

Affiliation

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.

中文翻译：

他莫昔芬是一种候选的一流酸性神经酰胺酶抑制剂，可减少多倍体巨型癌细胞的无丝分裂，而肿瘤发生过程中尚未被认识到。

多倍体巨癌细胞 (PGCC) 是一种人们知之甚少的小肿瘤细胞亚群，人们越来越认识到它们在治疗耐药、转移和癌症复发中的关键作用。 PGCC 有潜力通过原始分裂或类分裂分裂产生后代，这使它们能够逃避抗有丝分裂损伤。我们最近证明这一过程需要鞘脂酶酸性神经酰胺酶 (ASAH1)。由于临床上尚无特定的 ASAH1 抑制剂，我们研究了通过脱靶效应干扰 ASAH1 功能的他莫昔芬是否具有独立于雌激素信号传导的潜在临床益处。我们的结果表明，他莫昔芬抑制前列腺癌、胶质母细胞瘤和黑色素瘤细胞中 PGCC 后代的产生。对两个州级癌症登记处的分析表明，他莫昔芬可以改善早期乳腺癌女性中发生的第二种非乳腺癌的生存结果。我们的结果表明，他莫昔芬可能对多种癌症具有临床益处，这种益处与雌激素信号无关，可能是由于它抑制酸性神经酰胺酶。因此，在未来的临床试验中应考虑将他莫昔芬作为潜在的一流治疗药物来抑制 PGCC 后代的产生。

更新日期：2020-03-05

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