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Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
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Targeting cancer stem cells with p53 modulators.

Zhan Zhang1, Ling Liu1,2, Roberto Gomez-Casal3,4

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

Oncotarget
|April 14, 2016
PubMed
Summary

Small molecular weight compounds (SMWC) targeting p53 show promise in reducing cancer stem cells (CSC) and sphere formation in vitro. However, in vivo studies combining SMWC with vaccines did not improve survival outcomes.

Keywords:
CP-31398P53 vaccinePRIMA-1T cellscancer stem cells

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cancer stem cells (CSCs) often over-express aldehyde dehydrogenase (ALDH), making ALDHbright cells a therapeutic target.
  • Loss of p53 function is a frequent event in cancer, and small molecular weight compounds (SMWC) can restore p53 function.
  • CP-31398 and PRIMA-1 are studied p53 SMWC with potential to impact CSCs.

Purpose of the Study:

  • To investigate the efficacy of p53 SMWC (CP-31398 and PRIMA-1) against ALDHbright CSCs in various human carcinoma cell lines.
  • To compare the in vitro effectiveness of these p53 SMWC against CSCs with conventional chemotherapeutic agents.
  • To evaluate the in vivo efficacy of a combination therapy involving p53 SMWC and p53-based vaccines in a mouse model.

Main Methods:

  • Utilized human breast, endometrial, and pancreas carcinoma cell lines with mutant or wild type (WT) p53.
  • Assessed CSC content and sphere formation in vitro following treatment with CP-31398 and PRIMA-1.
  • Compared treatment outcomes with cisplatin and gemcitabine.
  • Conducted in vivo studies using methylcholantrene (MCA)-treated mice with a combination of p53 SMWC and p53-based vaccines, analyzing survival endpoints.

Main Results:

  • CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation in vitro.
  • These p53 SMWC demonstrated superior in vitro efficacy against CSCs compared to cisplatin and gemcitabine.
  • Combination therapy with p53 SMWC and vaccines in mice did not yield improved survival compared to vaccine alone.

Conclusions:

  • p53 SMWC effectively target ALDHbright CSCs and inhibit their growth in vitro, offering a potential new avenue for cancer treatment.
  • The lack of enhanced efficacy in vivo may be attributed to complex interactions with immune cells expressing WT p53 or interference from the continuous MCA exposure.
  • Further research into p53 SMWC for cancer treatment is warranted, considering their significant impact on CSCs.