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.
Highlights
The cancer stem cell (CSC) concept posits the existence of a subpopulation of tumor cells that display “stem cell-like” properties, namely, self-renewal and high tumorigenic potential, including resistance to most currently employed chemo- and radiotherapies [1,2,3].Cancer stem cells (CSC) may be largely responsible for the failure of most conventional therapies to control cancer growth and metastases
The consensus is that no single marker adequately defines CSC, a considerable amount of data indicates that tumor cells which express elevated levels of aldehyde dehydrogenase (ALDH) activity, ALDHpositive cells, have been shown to have CSC-like properties, in particular, the ability to initiate tumor growth at low numbers in immunodeficient mice [6,7,8,9,10,11,12]
The sensitivity of a panel of human tumor cell lines comprised of two breast, three endometrial, and two pancreas carcinoma cell lines to CP-31398 and PRIMA-1 was investigated
Summary
The cancer stem cell (CSC) concept posits the existence of a subpopulation of tumor cells that display “stem cell-like” properties, namely, self-renewal and high tumorigenic potential, including resistance to most currently employed chemo- and radiotherapies [1,2,3].CSC may be largely responsible for the failure of most conventional therapies to control cancer growth and metastases. The consensus is that no single marker adequately defines CSC, a considerable amount of data indicates that tumor cells which express elevated levels of aldehyde dehydrogenase (ALDH) activity, ALDHpositive cells, have been shown to have CSC-like properties, in particular, the ability to initiate tumor growth at low numbers in immunodeficient mice [6,7,8,9,10,11,12]. The research focuses on tumor cells having 2X the mean fluorescence (MFI) of ALDHpositive cells in a tumor, a subpopulation shown to consist of > 90% ALDHpositive cells [19]
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