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NAMPT Inhibition Suppresses Cancer Stem-like Cells Associated with Therapy-Induced Senescence in Ovarian Cancer. | LitMetric

AI Article Synopsis

  • - Epithelial ovarian cancer (EOC) is a severe form of cancer often treated with platinum-based chemotherapy like cisplatin, which can lead to chemoresistance due to the development of cancer stem-like cells (CSCs) through a process called cellular senescence.
  • - Research shows that inhibiting nicotinamide phosphoribosyltransferase (NAMPT) can reduce senescence-associated CSCs that form after platinum chemotherapy, enhancing the effectiveness of this treatment in EOC cells.
  • - The study suggests combining NAMPT inhibitors, like FK866, with cisplatin could improve outcomes for EOC patients by decreasing CSCs and potentially preventing tumor relapse after treatment.

Article Abstract

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both and . Moreover, a combination of the NAMPT inhibitor FK866 and cisplatin improved the survival of EOC-bearing mice. These phenotypes correlated with inhibition of the CSCs signature, which consists of elevated expression of ALDH1A1 and stem-related genes, high aldehyde dehydrogenase activity, and CD133 positivity. Mechanistically, NAMPT regulates EOC CSCs in a paracrine manner through the senescence-associated secretory phenotype. Our results suggest that targeting NAMPT using clinically applicable NAMPT inhibitors, such as FK866, in conjunction with platinum-based chemotherapy represents a promising therapeutic strategy by suppressing therapy-induced senescence-associated CSCs. SIGNIFICANCE: This study highlights the importance of NAMPT-mediated NAD biosynthesis in the production of cisplatin-induced senescence-associated cancer stem cells, as well as tumor relapse after cisplatin treatment.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024650PMC
http://dx.doi.org/10.1158/0008-5472.CAN-19-2830DOI Listing

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