A novel aldh1a1 inhibitor targets cells with stem cell characteristics in ovarian cancer

Nkechiyere G. Nwani, Salvatore Condello, Yinu Wang, Wendy M. Swetzig, Emma Barber, Thomas Hurley, Daniela Matei

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional marker of CSCs in ovarian cancer (OC). ALDH activity is increased in cells grown as spheres versus monolayer cultures under differentiating conditions and in OC cells after treatment with platinum. Here, we describe the activity of CM37, a newly identified small molecule with inhibitory activity against ALDH1A1, in OC models enriched in CSCs. Treatment with CM37 reduced OC cells’ proliferation as spheroids under low attachment growth conditions and the expression of stemness-associated markers (OCT4 and SOX2) in ALDH+ cells fluorescence-activated cell sorting (FACS)-sorted from cell lines and malignant OC ascites. Likewise, siRNA-mediated ALDH1A1knockdown reduced OC cells’ proliferation as spheres, expression of stemness markers, and delayed tumor initiation capacity in vivo. Treatment with CM37 promoted DNA damage in OC cells, as evidenced by induction of γH2AX. This corresponded to increased expression of genes involved in DNA damage response, such as NEIL3, as measured in ALDH+ cells treated with CM37 or in cells where ALDH1A1 was knocked down. By inhibiting ALDH1A1, CM37 augmented intracellular ROS accumulation, which in turn led to increased DNA damage and reduced OC cell viability. Cumulatively, our findings demonstrate that a novel ALDH1A1 small molecule inhibitor is active in OC models enriched in CSCs. Further optimization of this new class of small molecules could provide a novel strategy for targeting treatment-resistant OC.

Original languageEnglish (US)
Article number502
JournalCancers
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2019
Externally publishedYes

Fingerprint

Ovarian Neoplasms
Stem Cells
Aldehyde Dehydrogenase
DNA Damage
Cell Proliferation
Neoplastic Stem Cells
Tumor Biomarkers
Platinum
Ascites
Small Interfering RNA
Cell Survival
Flow Cytometry
Gene Expression
Recurrence
Cell Line
Growth

Keywords

  • ALDH1A1
  • Cancer stem cells
  • CM37
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A novel aldh1a1 inhibitor targets cells with stem cell characteristics in ovarian cancer. / Nwani, Nkechiyere G.; Condello, Salvatore; Wang, Yinu; Swetzig, Wendy M.; Barber, Emma; Hurley, Thomas; Matei, Daniela.

In: Cancers, Vol. 11, No. 4, 502, 01.04.2019.

Research output: Contribution to journalArticle

Nwani, Nkechiyere G. ; Condello, Salvatore ; Wang, Yinu ; Swetzig, Wendy M. ; Barber, Emma ; Hurley, Thomas ; Matei, Daniela. / A novel aldh1a1 inhibitor targets cells with stem cell characteristics in ovarian cancer. In: Cancers. 2019 ; Vol. 11, No. 4.
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abstract = "A small of population of slow cycling and chemo-resistant cells referred to as cancer stem cells (CSC) have been implicated in cancer recurrence. There is emerging interest in developing targeted therapeutics to eradicate CSCs. Aldehyde-dehydrogenase (ALDH) activity was shown to be a functional marker of CSCs in ovarian cancer (OC). ALDH activity is increased in cells grown as spheres versus monolayer cultures under differentiating conditions and in OC cells after treatment with platinum. Here, we describe the activity of CM37, a newly identified small molecule with inhibitory activity against ALDH1A1, in OC models enriched in CSCs. Treatment with CM37 reduced OC cells’ proliferation as spheroids under low attachment growth conditions and the expression of stemness-associated markers (OCT4 and SOX2) in ALDH+ cells fluorescence-activated cell sorting (FACS)-sorted from cell lines and malignant OC ascites. Likewise, siRNA-mediated ALDH1A1knockdown reduced OC cells’ proliferation as spheres, expression of stemness markers, and delayed tumor initiation capacity in vivo. Treatment with CM37 promoted DNA damage in OC cells, as evidenced by induction of γH2AX. This corresponded to increased expression of genes involved in DNA damage response, such as NEIL3, as measured in ALDH+ cells treated with CM37 or in cells where ALDH1A1 was knocked down. By inhibiting ALDH1A1, CM37 augmented intracellular ROS accumulation, which in turn led to increased DNA damage and reduced OC cell viability. Cumulatively, our findings demonstrate that a novel ALDH1A1 small molecule inhibitor is active in OC models enriched in CSCs. Further optimization of this new class of small molecules could provide a novel strategy for targeting treatment-resistant OC.",
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