A Novel ALDH1A1 Inhibitor Targets Cells with Stem Cell Characteristics in Ovarian Cancer

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Drug Discovery

Background:

• Cancer stem cells (CSCs) drive tumor recurrence and resistance to therapy.
• Aldehyde dehydrogenase (ALDH) activity is a marker for CSCs in ovarian cancer (OC).
• Targeting CSCs is crucial for developing effective ovarian cancer treatments.

Purpose of the Study:

• To investigate the efficacy of CM37, a novel ALDH1A1 inhibitor, against CSCs in ovarian cancer models.
• To elucidate the mechanisms by which CM37 affects CSCs and ovarian cancer progression.
• To evaluate CM37 as a potential therapeutic agent for treatment-resistant ovarian cancer.

Main Methods:

• Utilized ovarian cancer cell lines and patient-derived ascites enriched in CSCs.
• Administered CM37 and assessed its impact on spheroid proliferation, stemness markers (OCT4, SOX2), and ALDH1A1 expression.
• Employed siRNA-mediated ALDH1A1 knockdown and measured in vivo tumor initiation.
• Quantified DNA damage (γH2AX), DNA damage response gene expression (NEIL3), and reactive oxygen species (ROS) accumulation.

Main Results:

• CM37 treatment reduced ovarian cancer cell proliferation in spheroids and decreased stemness marker expression in ALDH+ CSCs.
• ALDH1A1 knockdown mimicked CM37 effects, reducing sphere formation, stemness, and tumor initiation.
• CM37 induced DNA damage, upregulated DNA damage response genes, and increased intracellular ROS.
• Inhibition of ALDH1A1 by CM37 led to increased ROS, DNA damage, and reduced cell viability.

Conclusions:

• CM37 is a novel small molecule inhibitor of ALDH1A1 with demonstrated activity against ovarian cancer models enriched in CSCs.
• CM37 effectively reduces CSC proliferation, stemness, and promotes DNA damage via ROS accumulation.
• Further development of ALDH1A1 inhibitors like CM37 holds promise for overcoming treatment resistance in ovarian cancer.