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Garcinia indica (Kokum) and Ilex aquifolium (European Holly)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Dicson Sheeja Malar, Mani Iyer Prasanth, Tewin Tencomnao, James Michael Brimson, Anchalee Prasansuklab
Garcinol exhibited morphological changes and inhibited the proliferation of human non-small cell lung carcinoma (NSCLC) cells. Garcinol induced G1 cell cycle arrest was mediated through the upregulation of CDK inhibitors p21Waf1/Cip1 and p27KIP1. Moreover, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), cyclin D1, and cyclin D3 were decreased, whereas cyclin E and cyclin-dependent kinase 6 (CDK6) were increased along with inhibition of ERK and p38-MAPK (Yu et al., 2014). In A549 cells, garcinol enriched DNA damage-inducible transcript 3 (DDIT3), altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in the attenuation of the prognostic cancer cell marker Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) expression (Wang et al., 2017a). In addition, garcinol significantly diminished the ability of the NSCLC cells to form spheres and form colonies, by impairing phosphorylation of LRP6, a co-receptor of Wnt and STAT3, downregulating β-catenin, Dvl2, Axin2, and cyclin D1 expressions, suggesting its ability to regulate the Wnt/β-catenin signaling pathway (Huang et al., 2018). Garcinol induced the sensitivity of A549 cells toward TRAIL and induced apoptosis mediated through upregulation of DR5 and downregulation c-FLIP (Kim et al., 2018).
Targeted Therapy for Cancer Stem Cells
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Rama Krishna Nimmakayala, Saswati Karmakar, Garima Kaushik, Sanchita Rauth, Srikanth Barkeer, Saravanakumar Marimuthu, Moorthy P. Ponnusamy
There are 19 ALDH proteins in humans, and many of these have a function related to cancers. Major functions of these proteins are to catalyze aldehyde oxidation, cellular detoxification, and protection from reactive oxygen species [9, 21]. It was shown that the β-catenin/TCF transcriptional complex directly binds to its target region on the promoter of ALDH1A1 gene suggesting that Wnt/β-catenin signaling regulates ALDH1A1 gene [22]. Also, MUC1-C (the cytosolic side of MUC1) activates ERK-C/EBPβ-ALDH1A1 signaling axis leading to the induction of ALDH activity in breast cancer [23]. CSCs also hold an efficient inactivation system to eradicate ROS. Studies show that ALDH protects drug-tolerant cell population from increased levels of ROS, conferring an additional resistance to CSCs against therapeutic drugs [24].
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Danuta Balicki, Brian Leyland-Jones, Max S. Wicha
As a result of the growing interest of identifying new markers for identifying and isolating stem cells, assays based on ALDH activity have been proposed to be a promising alternative in both murine and human mammary stem cells. ALDH is a family of cytosolic enzyme isoforms responsible for oxidizing intracellular aldehydes, including vitamin A, to carboxylic acids. It is highly expressed in hematopoietic progenitors, in intestinal crypt cells, as well as in breast tumor cells (54–56). ALDH1 or (ALDH isoenzyme 1 or ALDH1A1) has been shown to be responsible for the resistance observed in hematopoietic stem cells and breast cancer tumor cells to the alkylating agent, cyclophosphamide (56–58). A novel system has been designed to detect ALDH using a visible light excitable fluorochrome named Aldefluor® (BODIPY-conjugated aminoacetaldehyde, BAAA) metabolized by both murine and human cells (59). Fluorescence-activated cell sorter (FACS) of the normal breast cell population revealed that 6% of this population is ALDH-positive (60). In breast cancer cell lines, ALDH-positive cells were more frequently observed in basal-like than in luminal cell lines. ALDH-positive cells form mammospheres at a high efficiency and are tumorigenic in NOD/SCID mice (61).
Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer
Published in Nutrition and Cancer, 2022
Malihe Mohamadian, Afsane Bahrami, Maryam Moradi Binabaj, Fereshteh Asgharzadeh, Gordon A. Ferns
It is well established that the Wnt/β-catenin signaling pathway is important in carcinogenesis and cancer cell proliferation (68, 69). Curcumin has moderate cytotoxicity in both SKOV3 and OVCAR3 cells from the spheroids, according to an MTT experiment. Curcumin therapy (60 µM) resulted in a significant decrease in Aldehyde Dehydrogenase one Family Member A1 (ALDH1A1) expression as well as a total disruption of epithelial OC spheroids (EOC) cell sphere formation. ALDH1A1 is a marker of cancer stem cells and ALDH1A1/β-catenin interplay triggers spheroid formation (70, 71). In addition to subverting the sphere-forming capacity, curcumin significantly inhibited the adhesion and mesothelial invasiveness of OC spheroids (72). It has been reported that high fascin expression is related to poor prognosis and metastasis in different types of cancers (73, 74). Curcumin can suppress fascin expression through STAT3 inhibition in SKOV3 cells, which ultimately decreases cell migration and invasion in OC cells (44).
The shifting paradigm of colorectal cancer treatment: a look into emerging cancer stem cell-directed therapeutics to lead the charge toward complete remission
Published in Expert Opinion on Biological Therapy, 2021
Jessica Kopenhaver, Madison Crutcher, Scott A. Waldman, Adam E. Snook
Aldehyde dehydrogenase isoform 1 (mainly ALDH1A1, ALDH1A2 and ALDH1A3), is a cytosolic enzyme that catalyzes the conversion of aldehyde to carboxylic acid, and is involved in retinoid signaling pathways [49]. This enzyme is found in embryonic stem cells, normal intestinal stem cells, and is highly expressed in the liver. ALDH1 enzymes oxidize cytoplasmic rentinal to retinoic acid (RA), which translocates into the nucleus and acts as a co-activator for genes involved in self-renewal, tumor proliferation, and apoptosis resistance [49]. Furthermore, ALDH1 and other ALDH isoforms reduce ROS and reactive aldehydes, promoting tumor growth, preventing apoptotic pathway activation, and inciting oncogenesis in CSCs [50]. Additionally, ALDH1 mediates drug resistance in colorectal CSCs, and in rectal cancer, preoperative radio-chemotherapy induces expression of ALDH1 [51,52]. Moreover, in established colorectal cell lines, treatment with chemotherapeutic agents upregulates ALDH1 activity, enhancing resistance to ROS-induced stress and gene enrichment related to DNA damage, MAPK, FAK, oxidative stress response, and Wnt signaling [53].
Moonlighting in drug metabolism
Published in Drug Metabolism Reviews, 2021
ALDH1A1 is a homotetrameric enzyme that catalyzes the NAD+-dependent oxidation of aldehydes to carboxylic acids and the hydrolysis of esters, including nitrate esters (Sladek 2003; Marchitti et al. 2008). Cytosolic ALDH1A1 is widely distributed in human tissue with high expression in the stomach and epididymis and medium expression in the liver (The Human Protein Atlas ALDH1A1). ALDH1A1 is also highly expressed in the human lenticular and corneal tissues in a range of species (King and Holmes 1997; Manzer et al. 2003). η-Crystallin from the elephant shrew (Elephantulus edwardii) lens has been identified as a class 1 ALDH (Graham et al. 1996; Bateman et al. 2003). η-Crystallin is structurally similar to other class 1 ALDHs but with a more rigid cofactor binding site and a larger substrate binding site; retinal is a substrate for η-crystallin.