Expression and regulation of aldehyde dehydrogenases in prostate cancer

Ibrahim, Ali Mohamed; Sadiq, Muhammad; Frame, Fiona M.; Maitland, Norman J.; Pors, Klaus

doi:10.20517/2394-4722.2018.07

Cited by 7 publications

(9 citation statements)

References 195 publications

(259 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1C). These results suggest that regulation of the ALDH activity cannot be solely explained by the level of gene expression but also attributed to the posttranslational protein modifications as showed previously (Ibrahim et al, 2018). Since ALDH + cells exhibit stem-like properties, we next analyzed an association of ALDH1A1 and ALDH1A3 with CSC phenotype under serum-free sphere-forming conditions.…”

Section: Resultssupporting

confidence: 81%

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Gorodetska

Offermann

Pueschel

et al. 2021

Preprint

View full text Add to dashboard Cite

Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and β-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease.

show abstract

Section: Resultssupporting

confidence: 81%

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Gorodetska

Offermann

Pueschel

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…ALDHs have also been linked to chemo- and radioresistance in cancer therapy. 40 , 41 An increased expression of ALDH can have a chemoprotective effect on cells due to their metabolic and detoxifying abilities [reviewed in ref ( 41 )]. The taxanes paclitaxel and docetaxel have been reported to be less effective in ALDH-expressing cells.…”

Section: Resultsmentioning

confidence: 99%

Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer

et al. 2022

Self Cite

View full text Add to dashboard Cite

Aldehyde dehydrogenases (ALDHs) are overexpressed in various tumor types including prostate cancer and considered a potential target for therapeutic intervention. 4-(Diethylamino)benzaldehyde (DEAB) has been extensively reported as a pan-inhibitor of ALDH isoforms, and here, we report on the synthesis, ALDH isoform selectivity, and cellular potencies in prostate cancer cells of 40 DEAB analogues; three analogues ( 14 , 15 , and 16 ) showed potent inhibitory activity against ALDH1A3, and two analogues ( 18 and 19 ) showed potent inhibitory activity against ALDH3A1. Significantly, 16 analogues displayed increased cytotoxicity (IC 50 = 10–200 μM) compared with DEAB (>200 μM) against three different prostate cancer cell lines. Analogues 14 and 18 were more potent than DEAB against patient-derived primary prostate tumor epithelial cells, as single agents or in combination treatment with docetaxel. In conclusion, our study supports the use of DEAB as an ALDH inhibitor but also reveals closely related analogues with increased selectivity and potency.

show abstract

“…PCSCs constitute a rare population of cells, which are quiescent and do not seem to express AR [37] and hence are less sensitive to M-phase cell cycle targeting taxanes such as docetaxel and cabazitaxel or drugs such as enzalutamide and abiraterone targeting the biosynthetic steroidogenic pathway. Accordingly, new therapies are required to target and eradicate the PCSC subpopulation and ALDHs have been proposed as a potential target [22,38]. Several medicinal chemistry efforts are underway which have proven the possibility of targeting specific ALDH isoforms.…”

Section: Aldh Inhibitors Of the Imidazo[12-a]pyridine Series Have Anti-proliferative Effects Against Different Prostatic Tissue-derived Cmentioning

confidence: 99%

“…Various cell surface proteins, including CD44 [19], α2β1 integrin [20], and CD133 [21], as well as enzymes like aldehyde dehydrogenases (ALDHs) [22], have been useful in helping to identify CSC populations. Besides playing a key role as a molecular marker for tracking stem-like cells within the tumor bulk, ALDHs have also been linked to chemo-and radio-resistance [23,24] while their expression provides an opportunity for therapeutic intervention [25].…”

Section: Introductionmentioning

confidence: 99%

Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable Target

et al. 2020

Self Cite

View full text Add to dashboard Cite

Prostate cancer represents the most common malignancy diagnosed in men, and is the second-leading cause of cancer death in this population. In spite of dedicated efforts, the current therapies are rarely curative, requiring the development of novel approaches based on innovative molecular targets. In this work, we validated aldehyde dehydrogenase 1A1 and 1A3 isoform expressions in different prostatic tissue-derived cell lines (normal, benign and malignant) and patient-derived primary prostate tumor epithelial cells, demonstrating their potential for therapeutic intervention using a small library of aldehyde dehydrogenase inhibitors. Compound 3b, 6-(4-fluorophenyl)-2-phenylimidazo [1,2-a]pyridine exhibited not only antiproliferative activity in the nanomolar range against the P4E6 cell line, derived from localized prostate cancer, and PC3 cell lines, derived from prostate cancer bone metastasis, but also inhibitory efficacy against PC3 colony-forming efficiency. Considering its concomitant reduced activity against normal prostate cells, 3b has the potential as a lead compound to treat prostate cancer by means of a still untapped molecular target.

show abstract

Expression and regulation of aldehyde dehydrogenases in prostate cancer

Cited by 7 publications

References 195 publications

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases

Expansion of the 4-(Diethylamino)benzaldehyde Scaffold to Explore the Impact on Aldehyde Dehydrogenase Activity and Antiproliferative Activity in Prostate Cancer

Aldehyde Dehydrogenases and Prostate Cancer: Shedding Light on Isoform Distribution to Reveal Druggable Target

Contact Info

Product

Resources

About