Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

Abstract

Gynecologic cancers cause over 600,000 deaths annually in women worldwide. The development of chemoresistance after initial rounds of chemotherapy contributes to tumor relapse and death due to gynecologic malignancies. In this regard, cancer stem cells (CSCs), a subpopulation of stem cells with the ability to undergo self-renewal and clonal evolution, play a key role in tumor progression and drug resistance. Aldehyde dehydrogenases (ALDH) are a group of enzymes shown to be robust CSC markers in gynecologic and other malignancies. These enzymes also play functional roles in CSCs, including detoxification of aldehydes, scavenging of reactive oxygen species (ROS), and retinoic acid (RA) signaling, making ALDH an attractive therapeutic target in various clinical scenarios. In this review, we discuss the critical roles of the ALDH in driving stemness in different gynecologic malignancies. We review inhibitors of ALDH, both general and isoform-specific, which have been used to target CSCs in gynecologic cancers. Many of these inhibitors have been shown to be effective in preclinical models of gynecologic malignancies, supporting further development in the clinic. Furthermore, ALDH inhibitors, including 673A and CM037, synergize with chemotherapy to reduce tumor growth. Thus, ALDH-targeted therapies hold promise for improving patient outcomes in gynecologic malignancies.

ZIP4 Is a Novel Cancer Stem Cell Marker in High-Grade Serous Ovarian Cancer

“…These cells contained 2.8–10.0% ZIP4 + cells ( Figure 2 A). As a comparison, ALDH activity sorting was also included, since it is widely accepted as an EOC CSC marker [ 7 , 36 ] ( Figure 2 A). These cells contained 1–6% ALDH + cells, consistent with a previous publication [ 37 ].…”

Dichloroacetate attenuates the stemness of colorectal cancer cells via trigerring ferroptosis through sequestering iron in lysosomes

“…Additionally, DCA treatment inhibited the expression of stemness master regulators (Oct4, CD133, Sox2) (Figure 1E‐H). Furthermore, ALDH activity was suppressed in CRC cells treated with DCA, which has been shown to be markedly higher in CSC than in parental cancer cells 29,30 (Figure 1I).…”

The Great Escape: The Power of Cancer Stem Cells to Evade Programmed Cell Death

“…It has been reported that DS inhibits the P-gp extrusion pump, blocks NF-κB, sensitizes to chemotherapy, decreases angiogenesis, and reduces tumor growth in mice [ 215 ]. DS is able to inhibit both ALDH2 and ALDH1 isozymes, which are upregulated in CSCs, suggesting the potential use of DS as an antineoplastic drug [ 237 ]. Numerous papers have reported DS anti-cancer effects in different tumors (widely reviewed in [ 216 , 217 ]).…”