Disulfiram Transcends ALDH Inhibitory Activity When Targeting Ovarian Cancer Tumor-Initiating Cells

Caminear, Michael W; Harrington, Brittney S.; Kamdar, Rahul; Kruhlak, Michael J.; Annunziata, Christina M.

doi:10.3389/fonc.2022.762820

Cited by 12 publications

(19 citation statements)

References 35 publications

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“…Numerous genes associated with stemness have been reported to be characteristic of OCSCs [ 30 , 31 ]. It was observed that 974 significantly decreased the expression of the well-known stemness genes Bmi-1, Nanog, Oct4, and Sox2 in OVCAR3 ( Figure 2 C) and OVCAR5 cells ( Figure 2 D).…”

Section: Resultsmentioning

confidence: 99%

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Muralikrishnan

Fang

Given

et al. 2022

Cancers

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Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound 974, and used 974 as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with 974 significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that 974 significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with 974 revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that 974 inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation.

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Section: Resultsmentioning

confidence: 99%

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Muralikrishnan

Fang

Given

et al. 2022

Cancers

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“…During the peritoneal dissemination, addition of genetic mutations and chromosomal aberrations are minimal, whereas the epigenetic dynamics facilitates the phenotypic plasticity of HGSC for adaptation to various microenvironments. Clinical trials for new drugs targeting the peritoneal dissemination of ovarian cancer are in preparation or ongoing [ 16 88 89 90 91 92 93 ] ( Table 1 ). Further studies on the dynamic biology of HGSC cells are needed to develop the epoch-making methods for prevention, early detection, and treatment for HGSC.…”

Section: Discussionmentioning

confidence: 99%

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

et al. 2022

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Epithelial ovarian cancer remains the lethal gynecological malignancy in women. The representative histotype is high-grade serous carcinoma (HGSC), and most patients with HGSC present at advanced stages with peritoneal dissemination. Since the peritoneal dissemination is the most important factor for poor prognosis of the patients, complete exploration for its molecular mechanisms is mandatory. In this narrative review, being based on the clinical, pathologic, and genomic findings of HGSC, chromosomal instability and epigenetic dynamics have been discussed as the potential drivers for cancer development in the fallopian tube, acquisition of cancer stem cell (CSC)-like properties, and peritoneal metastasis of HGSC. The natural history of carcinogenesis with clonal evolution, and adaptation to microenvironment of peritoneal dissemination of HGSC should be targeted in the novel development of strategies for prevention, early detection, and precision treatment for patients with HGSC.

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“…Cells were washed in PBS and resuspended in 400µl PBS for analysis on a BD FACSVerse cell analyzer (BD Biosciences, Franklin Lakes, NJ). Cell death was assessed by Annexin V (640905, Biolegend, San Diego, CA) and propidium iodide (PI) (R37169, Thermo Scientific, Waltham, MA) staining on cells treated as indicated, as previously described (30,50).…”

Section: Cytokine Arraymentioning

confidence: 99%

“…Cell lines and culture conditions Ovarian cancer lines were obtained as gifts, or from ATCC or NCI-60 as described and were cultured as described (53). TIC-enriching spheroid culture conditions are previously described (30,47,50). Briefly, spheroids were generated by maintaining cells in ultra-low attachment (ULA) plates or flasks (Corning, Corning, NY) in defined medium.…”

Section: Immunohistochemistry and Quantificationmentioning

confidence: 99%

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UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

Harrington

Kamdar

Korrapati

et al. 2022

Preprint

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Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix (ECM) and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Immunohistochemistry was used to delineate UGDH expression in histological and molecular subtypes of EOC. High UGDH expression was observed in the majority of high-grade serous ovarian cancers and variable expression was observed in clear cell, mucinous and endometrioid histotypes. A distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype, where high UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Ovarian cancer cell lines were subtyped according to the molecular subtypes, and we examined the effect of modulating UGDH expression in cell lines representing the C1/mesenchymal subtype the C4/Differentiated subtype. Knockdown of UGDH in the C1/Mesenchymal subtype reduced spheroid viability, sphere-formation and reduced the CD133+/ALDH high TIC population. Conversely, overexpression of UGDH in the differentiated subtype reduced the TIC population. Inflammatory cytokine expression was altered by UGDH expression. In co-culture models, altering UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins. The effect of UGDH knockdown or overexpression in the C1/ mesenchymal and C4/differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH reduced tumor burden in C1/mesenchymal compared to controls. These data show that modulation of UGDH expression in tumors influences cells in the microenvironment and reveals distinct roles for UGDH in the mesenchymal and differentiated molecular subtypes of EOC. UGDH is a strong prospective therapeutic target in TICs, for the treatment of metastatic and recurrent EOC, particularly in patients with the mesenchymal molecular subtype.

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Disulfiram Transcends ALDH Inhibitory Activity When Targeting Ovarian Cancer Tumor-Initiating Cells

Cited by 12 publications

References 35 publications

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

A Novel ALDH1A1 Inhibitor Blocks Platinum-Induced Senescence and Stemness in Ovarian Cancer

Peritoneal dissemination of high-grade serous ovarian cancer: pivotal roles of chromosomal instability and epigenetic dynamics

UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

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