CD133+ tumor initiating cells in a syngenic murine model of pancreatic cancer respond to Minnelide.

Abstract

PURPOSE:

Pancreatic adenocarcinoma is the fourth leading cause for cancer-related mortality with a survival rate of less than 5%. Late diagnosis and lack of effective chemotherapeutic regimen contribute to these grim survival statistics. Relapse of any tumor is largely attributed to the presence of tumor-initiating cells (TIC) or cancer stem cells (CSC). These cells are considered as hurdles to cancer therapy as no known chemotherapeutic compound is reported to target them. Thus, there is an urgent need to develop a TIC-targeted therapy for pancreatic cancer.

EXPERIMENTAL DESIGN:

We isolated CD133(+) cells from a spontaneous pancreatic ductal adenocarcinoma mouse model and studied both surface expression, molecular markers of pancreatic TICs. We also studied tumor initiation properties by implanting low numbers of CD133(+) cells in immune competent mice. Effect of Minnelide, a drug currently under phase I clinical trial, was studied on the tumors derived from the CD133(+) cells.

RESULTS:

Our study showed for the first time that CD133(+) population demonstrated all the molecular markers for pancreatic TIC. These cells initiated tumors in immunocompetent mouse models and showed increased expression of prosurvival and proinvasive proteins compared to the CD133(-) non-TIC population. Our study further showed that Minnelide was very efficient in downregulating both CD133(-) and CD133(+) population in the tumors, resulting in a 60% decrease in tumor volume compared with the untreated ones.

CONCLUSION:

As Minnelide is currently under phase I clinical trial, its evaluation in reducing tumor burden by decreasing TIC as well as non-TIC population suggests its potential as an effective therapy.

• Authors: Sulagna Banerjee, Alice Nomura, Veena Sangwan, Rohit Chugh, Vikas Dudeja, Selwyn M Vickers, Ashok Saluja
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 9 Pg. 2388-99 (May 01 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24634377 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 AACR.

Chemical References

• AC133 Antigen
• Antigens, CD
• Antigens, Surface
• Antineoplastic Agents
• Diterpenes
• Epoxy Compounds
• Glycoproteins
• NF-kappa B
• Organophosphates
• Peptides
• Phenanthrenes
• Prom1 protein, mouse
• 14-O-phosphonooxymethyltriptolide disodium salt

Topics

• AC133 Antigen
• Animals
• Antigens, CD (genetics, metabolism)
• Antigens, Surface (metabolism)
• Antineoplastic Agents (administration & dosage, pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects, genetics)
• Cell Transformation, Neoplastic (genetics, metabolism)
• Disease Models, Animal
• Diterpenes
• Epoxy Compounds
• Gene Expression
• Glycoproteins (genetics, metabolism)
• Immunophenotyping
• Mice
• Mice, Transgenic
• NF-kappa B (metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Organophosphates (administration & dosage, pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Peptides (genetics, metabolism)
• Phenanthrenes (administration & dosage, pharmacology)
• Phenotype