Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.

Autor: Koksalar Alkan F; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA., Caglayan AB; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA., Alkan HK; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA., Benson E; Georgia Cancer Center, Department of Biochemistry, Augusta University, Augusta, GA, USA., Gunduz YE; Regenerative and Restorative Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Department of Physiology, International School of Medicine, Medipol University, Istanbul, Turkey., Sensoy O; Regenerative and Restorative Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Department of Physiology, International School of Medicine, Medipol University, Istanbul, Turkey., Durdagi S; Department of Pharmaceutical Chemistry, School of Pharmacy, Bahcesehir University, Istanbul, Turkey., Zarbaliyev E; Department of Surgery, Gaziosmanpasa Hospital Istanbul, Istanbul Yeni Yuzyil University, Istanbul, Turkey., Dyson G; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA., Assad H; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA., Shull A; Department of Biology, Presbyterian College, Clinton, SC, USA., Chadli A; Georgia Cancer Center, Department of Biochemistry, Augusta University, Augusta, GA, USA., Shi H; Georgia Cancer Center, Department of Biochemistry, Augusta University, Augusta, GA, USA., Ozturk G; Regenerative and Restorative Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Department of Physiology, International School of Medicine, Medipol University, Istanbul, Turkey., Korkaya H; Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, HWCRC 723 4100 John R. Street, Detroit, MI, 48201, USA. korkayah@karmanos.org.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Sep 28; Vol. 14 (1), pp. 22487. Date of Electronic Publication: 2024 Sep 28.
DOI: 10.1038/s41598-024-72989-6
Abstrakt: Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge. Minnelide, a prodrug of triptolide currently being tested in clinical trials, has shown anti-tumorigenic activity in multiple malignancies via targeting super enhancers, Myc and anti-apoptotic pathways such as HSP70. Distinct super-enhancer landscape drives cancer stem cells (CSC) in TNBC subtype while inducing immune suppressive TME. We show that Minnelide selectively targets CSCs in human and murine TNBC cell lines compared to cell lines of luminal subtype by targeting Myc and HSP70. Minnelide in combination with cyclophosphamide significantly reduces the tumor growth and eliminates metastasis by reprogramming the tumor microenvironment and enhancing cytotoxic T cell infiltration in 4T1 tumor-bearing mice. Resection of residual tumors following the combination treatment leads to complete eradication of disseminated tumor cells as all mice are free of local and distant recurrences. All control mice showed recurrences within 3 weeks of post-resection while single Minnelide treatment delayed recurrence and one mouse was free of tumor. We provide evidence that Minnelide targets tumor intrinsic pathways and reprograms the immune suppressive microenvironment. Our studies also suggest that Minnelide in combination with cyclophosphamide may lead to durable responses in patients with basal/TNBC subtype warranting its clinical investigation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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