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San Diego, CA, United States

Karimi-Busheri F.,University of Alberta | Karimi-Busheri F.,NovaRx Corporation | Rasouli-Nia A.,University of Alberta | Mackey J.R.,University of Alberta | Weinfeld M.,University of Alberta
Breast Cancer Research | Year: 2010

Introduction: A subpopulation of cancer cells, tumor-initiating cells, is believed to be the driving force behind tumorigenesis and resistance to radiation and chemotherapy. The persistence of tumor-initiating cells may depend on altered regulation of DNA damage and checkpoint proteins, as well as a reduced propensity to undergo apoptosis or senescence.Methods: To test this hypothesis, we isolated CD24-/low/CD44+tumor-initiating cells (as mammospheres) from MCF-7 breast cancer cells grown in adherent monolayer culture, and carried out a comprehensive comparison of cell death and DNA damage response pathways prior to and after exposure to ionizing radiation in mammospheres and monolayer MCF-7 cells. Single and double-strand break repair was measured by single-cell gel electrophoresis. The latter was also examined by phosphorylation of histone H2AX and formation of 53BP1 and Rad51 foci. Apoptosis was quantified by flow-cytometric analysis of annexin V-binding and senescence was analyzed on the basis of cellular β-galactosidase activity. We employed the telomeric repeat amplification protocol to quantify telomerase activity. Expression of key DNA repair and cell cycle regulatory proteins was detected and quantified by western blot analysis.Results: Our data demonstrate that in comparison to the bulk population of MCF-7 cells (predominantly CD24+/CD44+), the MCF-7 mammosphere cells benefit from a multifaceted approach to cellular protection relative to that seen in monolayer cells, including a reduced level of reactive oxygen species, a more active DNA single-strand break repair (SSBR) pathway, possibly due to a higher level of expression of the key SSBR protein, human AP endonuclease 1 (Ape1), and a significantly reduced propensity to undergo senescence as a result of increased telomerase activity and a low level of p21 protein expression. No significant difference was seen in the rates of double-strand break repair (DSBR) between the two cell types, but DSBR in mammospheres appears to by-pass the need for H2AX phosphorylation.Conclusions: Enhanced survival of MCF-7 tumor-initiating cells in response to ionizing radiation is primarily dependent on an inherent down-regulation of the senescence pathway. Since MCF-7 cells are representative of cancer cells that do not readily undergo apoptosis, consideration of senescence pathways may play a role in targeting stem cells from such tumors. © 2010 Karimi-Busheri et al.; licensee BioMed Central Ltd. Source


A universal vaccine containing a mixture of allogeneic cell lines, including tumor stem cells, effective against tumors regardless of type is disclosed. The cell lines are also modified to prevent interference with the immune response by any immunosuppressive agents they may secrete.


Patent
NovaRx Corporation | Date: 2012-12-21

Methods, compositions and compounds that include a nucleic acid comprising a sequence consisting essentially of polyT/polyU and an agent that inhibits the production or activity of an immunosuppressive compound for treating tumors are described.


Patent
NovaRx Corporation | Date: 2013-03-13

Compounds that are specifically toxic to cancer stem cells are disclosed.


Patent
NovaRx Corporation | Date: 2013-03-13

Compounds that are specifically toxic to cancer stem cells are disclosed.

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