Minnelide effectively eliminates CD133+ side population in pancreatic cancer

Molecular Cancer

Research

Alice Nomura¹  Veena Sangwan¹  Olivia McGinn¹  Vikas Dudeja¹  Ashok K. Saluja²  Sulagna Banerjee² 

[1] Department of Surgery, Division of Basic and Translational Research, University of Minnesota, 55455, Minneapolis, MN, USA;Department of Surgery, Division of Basic and Translational Research, University of Minnesota, 55455, Minneapolis, MN, USA;Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA;

关键词: Pancreatic Cancer;    Cancer Stem Cell;    Side Population;    Pancreatic Cancer Cell Line;    Athymic Nude Mouse;   

DOI  :  10.1186/s12943-015-0470-6

 received in 2015-06-25, accepted in 2015-11-10,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundPancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease hallmarked by limited patient survival. Resistance to chemotherapy, a major cause of treatment failure in PDAC patients, is often attributed to Cancer Stem Cells (CSCs). Pancreatic CSCs are a small subset of quiescent cells within a tumor represented by surface markers like CD133. These cells are responsible not only for tumor recurrence, but also poor prognosis based on their “stem-like” characteristics. At present, conventional therapy is directed towards rapidly dividing PDAC cells and thus fails to target the CSC population.MethodsMIA PaCa-2, S2-013 and AsPC-1 were treated with 12.5 nM triptolide (12 T cells) for 7 days. The surviving cells were recovered briefly in drug-free growth media and then transferred to Cancer Stem cell Media (CSM). As a control, untreated cells were also transferred to CSM media (CSM). The 12 T and CSM cells were tested for stemness properties using RNA and protein markers. Low numbers of CSM and 12 T cells were implanted subcutaneously in athymic nude mice to study their tumorigenic potential. 12 T and CSM cells were sorted for CD133 expression and assayed for their colony forming ability and sphere forming ability. Invasiveness of 12 T cells, CSM and MIA PaCa-2 were compared using Boyden chamber assays.ResultsTreated 12 T cells displayed increased expression of the surface marker CD133 and the drug transporter ABCG2 compared to untreated cells (CSM cells). Both 12 T and CSM cells formed subcutaneous tumors in mice confirming their tumor-initiating properties. When tested for invasion, 12 T cells had increased invasiveness compared to CSM cells. CD133+ cells in both CSM and 12 T showed greater colony and sphere forming ability compared to CD133− cells from each group. Consistent with these data, when injected subcutaneously in mice, CD133− cells from CSM or 12 T did not form any tumors whereas CD133+ cells from both groups showed tumor formation at a very low cell number. Despite pre-exposure to triptolide in 12 T CD133+ cells, treatment of tumors formed by these cells with Minnelide, a triptolide pro-drug, showed significant tumor regression.ConclusionOur results indicated that triptolide enhanced and enriched the “stemness” in the PDAC cell lines at a low dose of 12.5 nM, but also resulted in the regression of tumors derived from these cells.

【 授权许可】

CC BY   
© Nomura et al. 2015