Oncotarget

Research Papers:

Targeting cancer stem cells with p53 modulators

Zhan Zhang _, Ling Liu, Roberto Gomez-Casal, Xinhui Wang, Ryo Hayashi, Ettore Appella, Levy Kopelovich and Albert B. DeLeo

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Oncotarget. 2016; 7:45079-45093. https://doi.org/10.18632/oncotarget.8650

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Abstract

Zhan Zhang1,*, Ling Liu1,2,*, Roberto Gomez-Casal3,4,*, Xinhui Wang2,*, Ryo Hayashi5, Ettore Appella5, Levy Kopelovich6, Albert B. DeLeo3,4

1Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

2Department of Surgery, Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

3University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

4Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

5National Cancer Institute, Bethesda, MD, USA

6Department of Medicine, Weill Cornell Medical College, New York, NY, USA

*These authors have contributed equally to this work

Correspondence to:

Xinhui Wang, e-mail: xwang30@mgh.harvard.edu

Keywords: CP-31398, PRIMA-1, cancer stem cells, P53 vaccine, T cells

Received: December 02, 2015    Accepted: March 18, 2016    Published: April 08, 2016

ABSTRACT

Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDHbright tumor cells represent targets for developing novel cancer prevention/treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified. Here, we focused on two widely studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast, endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT) p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by these cell lines in vitro. In addition, these agents were more effective in vitro against CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents. We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis, no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared to vaccine alone was observed. These results may be due, in part, to the presence of immune cells, such as activated lymphocytes expressing WT p53 at levels comparable to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter survival of these immune cells and negatively impact an effective immune response. Continuous exposure of mice to MCA may have also interfered with the action of these p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of p53 SMWC on CSC and cancer treatment remains of great interest.


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