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.

Keywords: aldehyde dehydrogenases; cancer stem cells; gynecologic malignancies.

Figure 1

Role of aldehyde dehydrogenases (ALDH) in cancer stem cells: ALDH detoxifies toxic aldehydes (endogenous and exogenous) into less toxic carboxylic acids. ALDH maintains intracellular reactive oxygen species (ROS) at a low level thus preventing oxidative stress and DNA damage. ALDH oxidizes retinaldehyde into retinoic acid, which promotes stemness, growth, and survival in cancer stem cells.

Figure 2

Site of gynecologic cancers in the female reproductive tract and statistics for incidence and mortality worldwide (2018) [58] and in USA [60].