Doxorubicin-enriched, ALDHbr mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1
Open Access
- 23 November 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 12 (1), 549
- https://doi.org/10.1186/1471-2407-12-549
Abstract
Background: The primary objective of this study was to test whether oncolytic herpes simplex virus type 1 (HSV1) could eradicate chemoresistant cancer stem cells (CSCs). Methods: The fluorescent aldefluor reagent-based technique was used to identify and isolate ALDHbr cells as CSCs from the 4T1 murine breast cancer cell line. The presence of ALDHbr 4T1 cells was also examined in 4T1 breast cancer transplanted in immune-competent syngeneic mice. Results: Compared with ALDHlo cells, ALDHbr cells had a markedly higher ability to form tumor spheres in vitro and a higher tumorigenic potential in vivo. ALDHbr cells also exhibited increased doxorubicin resistance in vitro, which correlated with a selective increase in the percentage of ALDHbr cells after doxorubicin treatment and an increased expression of P-glycoprotein (P-gp), a known chemoresistance factor. In contrast, oncolytic HSV1 was able to kill ALDHbr cells in vitro and even more markedly in vivo. Furthermore, in in vivo studies, systemic administration of doxorubicin followed by intratumoral injection of oncolytic HSV1 resulted in much more significant suppression of tumor growth with increased median survival period compared with each treatment given alone (p+ T lymphocytes were induced by oncolytic HSV1, no significant specific T cell response against CSCs was detected in vivo. Conclusions: These results suggested that the use of oncolytic HSV1 following doxorubicin treatment may help eradicate residual chemoresistant CSCs in vivo.Keywords
This publication has 74 references indexed in Scilit:
- Increased Expression of P-Glycoprotein Is Associated with Doxorubicin Chemoresistance in the Metastatic 4T1 Breast Cancer ModelThe American Journal of Pathology, 2011
- Single‐marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenaseHead & Neck, 2010
- Targeting Cancer-initiating Cells With Oncolytic VirusesMolecular Therapy, 2009
- Immunological aspects of cancer chemotherapyNature Reviews Immunology, 2008
- ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical OutcomeCell Stem Cell, 2007
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responsesProceedings of the National Academy of Sciences of the United States of America, 2006
- Tumour stem cells and drug resistanceNature Reviews Cancer, 2005
- Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and CardiotoxicityPharmacological Reviews, 2004
- Prospective identification of tumorigenic breast cancer cellsProceedings of the National Academy of Sciences of the United States of America, 2003