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- Title
Minnelide effectively eliminates CD133<sup>+</sup> side population in pancreatic cancer.
- Authors
Nomura, Alice; McGinn, Olivia; Dudeja, Vikas; Sangwan, Veena; Saluja, Ashok K.; Banerjee, Sulagna
- Abstract
Background: Pancreatic 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. Methods: MIA 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. Results: Treated 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. Conclusion: Our 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.
- Subjects
PANCREATIC cancer; CANCER stem cells; TRIPTOLIDE; CELL lines; CANCER invasiveness; TUMOR growth; RNA
- Publication
Molecular Cancer, 2015, Vol 14, Issue 1, p1
- ISSN
1476-4598
- Publication type
Article
- DOI
10.1186/s12943-015-0470-6