ALDH1A

The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette-Guérin (BCG). However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy for a subset of BC patients, these have failed to meet primary endpoints in clinical trials. Thus, it is crucial to find a new treatment...

Aldehyde dehydrogenase 1A (ALDH1A) isoforms may be a useful target for overcoming chemotherapy resistance in high-grade serous ovarian cancer (HGSOC) and other solid tumor cancers. However, as different cancers express different ALDH1A isoforms, isoform selective inhibitors may have a limited therapeutic scope. Furthermore, resistance to an ALDH1A isoform selective inhibitor could arise via induction of expression of other ALDH1A isoforms. As such, we have focused on the development of pan-ALDH1A inhibitors, rather than on ALDH1A isoform selective compounds...

The aldehyde dehydrogenase 1A1 (ALDH1A1) also known as retinal dehydrogenase, is an enzyme normally involved in the cellular metabolism, development and detoxification processes in healthy cells. However, it's also considered a cancer stem cell marker and its high levels of expression in several cancers, including breast, lung, ovarian, and colon cancer have been associated with poor prognosis and resistance to chemotherapy. Given its crucial role in chemotherapy resistance by detoxification of chemotherapeutic drugs, ALDH1A1 has attracted significant research interest as a potential therapeutic target for cancer...

OBJECTIVES: Retinoic acid plays diverse physiological and pathophysiological roles in reproduction, immune function, energy metabolism and carcinogenesis. Because of the potential benefits of inhibiting retinoic acid biosynthesis in certain disease states, efforts are underway to develop inhibitors of retinoic acid biosynthesis via inhibition of the aldehyde dehydrogenase-1 A (ALDH1A) family of enzymes. However, many potential ALDH1A inhibitors also inhibit the related ALDH2 enzyme that plays a role in the metabolism of ethanol...

INTRODUCTION: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by loss of expression of paternal chromosome 15q11.2-q13 genes. Individuals with PWS exhibit unique physical, endocrine, and metabolic traits associated with severe obesity. Identifying liver steatosis in PWS is challenging, despite its lower prevalence compared to non-syndromic obesity. Reliable biomarkers are crucial for the early detection and management of this condition associated with the complex metabolic profile and cardiovascular risks in PWS...

OBJECTIVES: We examined the return to fertility and transgenerational impact of treatment with WIN 18,446, an experimental male contraceptive, in mice. STUDY DESIGN: We paired male mice treated with WIN 18,446 for 4 weeks to suppress spermatogenesis followed by a nine-week recovery and mated them with normal females to assess fertility. F1 generation mice were subsequently mated to ascertain any transgenerational impact of treatment on fertility. Testes were examined histologically...

There are limited pharmacological treatment options for inflammatory bowel disease (IBD), and some of these options are expensive and administered by injection or infusion. Thus, new cheaper and easier (oral) treatment options are needed. ALDH1A enzymes produce retinoic acid that can affect intestinal diseases such as IBD by regulating immune cells in the gut. We previously demonstrated that an orally deliverable ALDH1A inhibitor, WIN 18,466, can suppress colitis in an acute mouse model of IBD. Here, we tested the efficacy of ALDH1A inhibition in a chronic mouse model of IBD...

BACKGROUND: Heterogeneous tumor cells are thought to be a significant factor in the failure of endocrine therapy in estrogen receptor-positive (ER+) cancers. Culturing patient-derived breast cancer cells (PDBCCs) provides an invaluable tool in pre-clinical and translational research for the heterogeneity of cancer cells. This study aimed to investigate the effects of different media components and culture methods on the BCSC-associated immunophenotypes and gene expression in ER + PDBCCs...

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models...

Cadmium (Cd), one of the most common contaminants in diet and drinking water, impairs testicular germ cell development and spermatogenesis. Autophagy is essential for maintaining Sertoli cell function and Sertoli-germ cell communication. However, the role of Sertoli cell autophagy in Cd-caused spermatogenesis disorder remains unclear. Here, the mice of autophagy-related gene 5 (Atg5) knockouts in Sertoli cells were used to investigate the effect of autophagy deficiency on Cd-impaired spermatogenesis and its underlying mechanisms...

Increased oxidative stress and neuroinflammation play a crucial role in the pathogenesis of Parkinson's disease (PD). In this study, the expression levels of 52 genes related to oxidative stress and inflammation were measured in peripheral blood mononuclear cells of the discovery cohort including 48 PD patients and 25 healthy controls. Four genes, including ALDH1A , APAF1 , CR1 , and CSF1R , were found to be upregulated in PD patients. The expression patterns of these genes were validated in a second cohort of 101 PD patients and 61 healthy controls...

Aldehyde dehydrogenase (ALDH) enzymes are involved in the growth and development of several tissues, including cancer cells. It has been reported that targeting the ALDH family, including the ALDH1A subfamily, enhances cancer treatment outcomes. Therefore, we aimed to investigate the cytotoxicity of ALDH1A3-affinic compounds that have been recently discovered by our group, on breast (MCF7 and MDA-MB-231) and prostate (PC-3) cancer cell lines. These compounds were investigated on the selected cell lines as single treatments and in combination with doxorubicin (DOX)...

Introduction: GIST (gastrointestinal stromal tumor) is the most prominent mesenchymal neoplasms of the gastrointestinal tract, and liver is the most common metastasis site for GIST. The molecular mechanism leading to liver metastasis of GIST is currently unclear. Methods: With the goal of revealing the underlying mechanism, we performed whole-genome gene expression profiling on 18 pairs of RNA samples comprised of GIST tissues (with liver metastasis) and corresponding non-tumor tissues. After identifying differentially expressed gene, functional annotation and signal pathway analyses were conducted...

Metastatic tumor is initiated by metastatic seeds (cancer stem cells "CSCs") in a controlled redox microenvironment. Hence, an effective therapy that disrupts redox balance with eliminating CSCs is critical. Diethyldithiocarbamate (DE) is potent inhibitor of radical detoxifying enzyme (aldehyde dehydrogenase "ALDH"1A) causing effective eradication of CSCs. This DE effect was augmented and more selective by its nanoformulating with green synthesized copper oxide (Cu4 O3 ) nanoparticles (NPs) and zinc oxide NPs, forming novel nanocomplexes of CD NPs and ZD NPs, respectively...

Recurrent disease and treatment-associated chemoresistance are the two main factors accounting for poor clinical outcomes of ovarian cancer (OC) patients. Both can be associated with cancer stem cells (CSCs), which contribute to cancer formation, progression, chemoresistance, and recurrence. Hence, this study investigated whether the expression of known CSC-associated markers ALDH1A, CD44, and CD133 may predict OC patient prognosis. We analyzed their expression in primary epithelial ovarian cancer (EOC) patients using immunohistochemistry and related them to clinicopathological data, including overall survival (OS) and progression-free survival (PFS)...

Objective: Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy. This study explored the mechanism of TAZ in regulating drug sensitivity of cisplatin (DDP-)-resistant EOC cells through the ANGPTL4/SOX2 axis. Methods: The A2780/DDP cells were prepared by stepwise progressive concentration method. The drug resistance and TAZ expression in EOC cells were determined. Drug sensitivity was measured after TAZ overexpression in A2780 cells and TAZ downregulation in A2780/DDP cells, respectively...

Glioblastoma (GBM) is the most aggressive primary brain tumour for which both effective treatments and efficient tools for an early-stage diagnosis are lacking. Herein, we present curcumin-based fluorescent probes that are able to bind to aldehyde dehydrogenase 1A3 (ALDH1A3), an enzyme overexpressed in glioma stem cells (GSCs) and associated with stemness and invasiveness of GBM. Two compounds are selective versus ALDH1A3, without showing any appreciable interaction with other ALDH1A isoenzymes. Indeed, their fluorescent signal is detectable only in our positive controls in vitro and absent in cells that lack ALDH1A3...

Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy...

Breast cancer is currently the second leading cause of death for women worldwide. One subtype of breast cancer with poor prognosis is triple-negative breast cancer (TNBC), which is characterized by the lack of expression of estrogen, progesterone, and human epidermal growth factor 2 (HER2) receptors. TNBC is difficult to treat due to its drug resistance and aggressiveness. Tumor invasiveness is driven by epithelial-mesenchymal transition (EMT), which allows cells to acquire mobility to metastasize. EMT is also relevant to maintaining cancer stem cell (CSC) characteristics...

The Adverse Outcome Pathway (AOP) concept is an emerging tool in regulatory toxicology that uses simplified descriptions to show cause-effect relationships between stressors and toxicity outcomes in intact organisms. The AOP structure is a modular framework, with Key Event Relationships (KERs) representing the unit of causal relationship based on existing knowledge, describing the connection between two Key Events. Because KERs are the only unit to support inference it has been argued recently that KERs should be recognized as the core building blocks of knowledge assembly within the AOP-Knowledge Base...