ALDEFLUOR activity, ALDH isoforms, and their clinical significance in cancers

Figures & data

Figure 1. Chemical structures of ALDH inhibitors.

Table 1. Different ALDH isoforms and their location in various cancer types.

Cancer types	ALDH isoform	Location	References
AML	ALDH1A1, ALDH3A1		67,71,72
	ALDH1A1		70,73–75
K562 cell line	ALDH1, ALDH3, ALDH5, ALDH6, ALDH7, and ALDH8		17
Breast cancer	ALDH1A1	Cytoplasmic/membranous	24,83,84,88
	ALDH1A3	Nuclear/cytoplasmic/membranous	66,86,90,91
	ALDH1A1, ALDH1A3	Cytoplasmic/membranous Nuclear/cytoplasmic/membranous	87
MDA-MB-435, MDA-MB-468 cells	ALDH1A3		66,90
BT-474 cells	ALDH1A1 ALDH2		63,88
MDA-MB-468, MDA-MB-231, SKBR-3 cells	ALDH1A1 ALDH1A3		66,88
BT-483, BT-20, MDA-MB-231, MDA-MB-436, MDA-MB-453, MDA-MB-157, MCF7, T47D, BT-549, ZR75-1, HCC202 and HCC1428 cells	ALDH1A1		88
MCF10A cells	ALDH1A3, ALDH3A2		63
Buccal carcinoma cell line SqCC/Y1	ALDH1A3, ALDH3A1, ALDH3A2, ALDH4A1, ALDH7A1, ALDH9A1		93
Colorectal cancer	ALDH1A1	Cytoplasmic/membranous	32–34,88
	ALDH1B1 ALDH1A1	Cytoplasmic/membranous Cytoplasmic/membranous	65
HCT-116 cells	ALDH1A3		34
LoVo, and BE cells	ALDH1A1		88
HT-29 cells	ALDH1A1		34,88
LS-180 cells	ALDH1A1 ALDH2		34
Pancreatic cancer	ALDH1A1	Cytoplasmic/membranous	43,94
AsPC-1, BxPC3	ALDH1A3		95
MIA PaCa cells	ALDH1A1 ALDH1A3		95
NSCLC	ALDH1A1	Cytoplasmic/membranous	37,38,98–101
	ALDH1A1 ALDH3A1	Cytoplasmic/membranous Cytoplasmic/membranous/nuclear	39,96,97
A549 cells	ALDH1A1		39
Calu-1, H358, H1993, H2009, H2087, HCC44, HCC95, and HCC827 cells	ALDH1A3		102
Melanoma	ALDH1A1 ALDH1A3	Cytoplasmic/membranous Cytoplasmic/membranous	104,105
1205Lu, A375, WM239A, and HS294T	ALDH1A1 ALDH1A3		104
Prostate cancer	ALDH1A1	Cytoplasmic/membranous	16,49,106
	ALDH7A1, ALDH3A2, ALDH4A1, ALDH9A1,	Cytoplasmic/membranous/nuclear Cytoplasmic/membranous/nuclear Cytoplasmic/membranous Cytoplasmic/membranous	106
	ALDH18A1	Cytoplasmic/membranous
	ALDH7A1	Cytoplasmic/membranous/nuclear	50
PC3 and LNCaP cells	ALDH1A1		49
HNSCC	ALDH1A1	Cytoplasmic/membranous	109
	ALDH1A3	Nuclear	110
FaDu and Cal33 cells	ALDH1A3		110
Liver cancer	ALDH1A1	Cytoplasmic/membranous	41,111
intrahepatic cholangiocarcinoma	ALDH1A3		40
HuCCT1 cells	ALDH1A3 ALDH1L1
SUN1079 cells	ALDH1A3, ALDH1B1, ALDH6A1, ALDH1A1, ALDH18A1, ALDH3B2, ALDH3B1
Hep3B, Huh7, H2M, PLC8024, Hep2B, Huh1 and Huh7 cell	ALDH1A1		111
Brain tumours
Glioma	ALDH1A1	Cytoplasmic/membranous	113
Glioma	ALDH1A3	Nuclear	114
U251 cells	ALDH1A1		113

Figure 2. The substrate binding positions of ALDH1A3 and ALDH2. Surface representation of ALDH1A3 (A, in gray); the conserved ligand-binding residues are occupied by G136, L471, and T315 (PDB:5FHZ). Surface representation of human mitochondrial ALDH2 (B, in pink), with positions 124, 459, and 303 shown (PDB:1O01). The binding sites from the two monomers are shown as sticks and coloured red, blue, and yellow according to their positions.

Figure 3. The expression levels of different ALDH family isoforms in 30 normal tissues. The data were derived from the GTEx (Genotype-Tissue Expression Project). Dendrograms and heat maps of ALDH mRNA expression in various normal tissues are shown.

Figure 4. Comparison of the expression levels of different ALDH subtypes in various tumour tissues and corresponding normal tissues. A heat map was generated based on a TCGA dataset. The dendrogram of tumours (top) was divided into 4 parts using different colours.

Table 2. Clinical trials on ALDH in cancers.

Description	Status	Conditions	Phase	Study Results	Trial identifier
Evaluation of the effectiveness of an aldehyde inhibitor Dehydrogenases (DIMATE) on the cell population of leukemic or normal stem cells	Recruiting	Leukaemia	Not Applicable	No Results Available	NCT02748850
Association of ALDH with disease incidence	Not yet recruiting	Oral Squamous Cell Carcinoma	Not Applicable	No Results Available	NCT04270201
CSCs marker	Completed	Breast Cancer	Not Applicable	No Results Available	NCT00949013
CSCs marker	Completed	Breast Cancer	II	Has Results	NCT01190345
CSCs marker	Completed	Breast Cancer	II	No Results Available	NCT01688609
CSCs marker	Completed	Breast Cancer	Early Phase 1	No Results Available	NCT04142892
CSCs marker	Completed	Healthy Lobular Breast Carcinoma in Situ	I	No Results Available	NCT01077453
CSCs marker	Completed	Breast Cancer	II, III	No Results Available	NCT01426880
CSCs marker	Completed	Lung Cancer, Non-small Cell Relapse/Recurrence CSC	Not Applicable	No Results Available	NCT04634630
CSCs marker	Completed	Lymphoma	II	Has Results	NCT00369681
CSCs marker	Completed	Ovarian Neoplasms, Fallopian Tube Neoplasms, Peritoneal Neoplasms	I	No Results Available	NCT02903771
CSCs marker	Completed	Pancreatic Cancer	I, II	No Results Available	NCT03410030

Yang X, Yao R, Wang H. Update of aldh as a potential biomarker and therapeutic target for aml. Biomed Res Int. 2018;2018:9192104.

 PubMed Web of Science ®Google Scholar

Gasparetto M, Smith CA. Aldhs in normal and malignant hematopoietic cells: potential new avenues for treatment of aml and other blood cancers. Chem Biol Interact. 2017;276:46–51.

 PubMed Web of Science ®Google Scholar

Pearce DJ, Taussig D, Simpson C, Allen K, Rohatiner AZ, Lister TA, Bonnet D. Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells. 2005;23(6):752–760.

 PubMed Web of Science ®Google Scholar

Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC, Vasiliou V. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med. 2013;56:89–101.

 PubMed Web of Science ®Google Scholar

Moreb JS, Ucar D, Han S, Amory JK, Goldstein AS, Ostmark B, Chang LJ. The enzymatic activity of human aldehyde dehydrogenases 1a2 and 2 (aldh1a2 and aldh2) is detected by aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance. Chem Biol Interact. 2012;195(1):52–60.

 PubMed Web of Science ®Google Scholar

Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, et al. Aldh1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–567.

 PubMed Web of Science ®Google Scholar

Zhao D, Mo Y, Li MT, Zou SW, Cheng ZL, Sun YP, Xiong Y, Guan KL, Lei QY. Notch-induced aldehyde dehydrogenase 1a1 deacetylation promotes breast cancer stem cells. J Clin Invest. 2014;124(12):5453–5465.

 PubMed Web of Science ®Google Scholar

Croker AK, Allan AL. Inhibition of aldehyde dehydrogenase (aldh) activity reduces chemotherapy and radiation resistance of stem-like aldhhicd44(+) human breast cancer cells. Breast Cancer Res Treat. 2012;133(1):75–87.

 PubMed Web of Science ®Google Scholar

Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, et al. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (aldh1), in human epithelial cancers. PLoS One. 2010;5(4):e10277.

 PubMed Web of Science ®Google Scholar

Marcato P, Dean CA, Giacomantonio CA, Lee PW. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle. 2011;10(9):1378–1384.

 PubMed Web of Science ®Google Scholar

Dehghan Harati M, Rodemann HP, Toulany M. Nanog signaling mediates radioresistance in aldh-positive breast cancer cells. Int J Mol Sci. 2019;20(5):1151.

 PubMed Web of Science ®Google Scholar

Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, Helyer L, Pan L, Leidal A, Gujar S, et al. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform aldh1a3 and its expression is predictive of metastasis. Stem Cells. 2011;29(1):32–45.

 PubMed Web of Science ®Google Scholar

Marcato P, Dean CA, Liu RZ, Coyle KM, Bydoun M, Wallace M, Clements D, Turner C, Mathenge EG, Gujar SA, et al. Aldehyde dehydrogenase 1a3 influences breast cancer progression via differential retinoic acid signaling. Mol Oncol. 2015;9(1):17–31.

 PubMed Web of Science ®Google Scholar

Moreb JS, Ucar-Bilyeu DA, Khan A. Use of retinoic acid/aldehyde dehydrogenase pathway as potential targeted therapy against cancer stem cells. Cancer Chemother Pharmacol. 2017;79(2):295–301.

 PubMed Web of Science ®Google Scholar

Zhou L, Sheng D, Wang D, Ma W, Deng Q, Deng L, Liu S. Identification of cancer-type specific expression patterns for active aldehyde dehydrogenase (aldh) isoforms in aldefluor assay. Cell Biol Toxicol. 2019;35(2):161–177.

 PubMed Web of Science ®Google Scholar

Hedberg JJ, Grafstrom RC, Vondracek M, Sarang Z, Warngard L, Hoog JO. Micro-array chip analysis of carbonyl-metabolising enzymes in normal, immortalised and malignant human oral keratinocytes. Cell Mol Life Sci. 2001;58(11):1719–1726.

 PubMed Web of Science ®Google Scholar

Chen Y, Orlicky DJ, Matsumoto A, Singh S, Thompson DC, Vasiliou V. Aldehyde dehydrogenase 1b1 (aldh1b1) is a potential biomarker for human colon cancer. Biochem Biophys Res Commun. 2011;405(2):173–179.

 PubMed Web of Science ®Google Scholar

Kozovska Z, Patsalias A, Bajzik V, Durinikova E, Demkova L, Jargasova S, Smolkova B, Plava J, Kucerova L, Matuskova M. Aldh1a inhibition sensitizes colon cancer cells to chemotherapy. BMC Cancer. 2018;18(1):656.

 PubMedGoogle Scholar

Rasheed Z, Wang Q, Matsui W. Isolation of stem cells from human pancreatic cancer xenografts. J Vis Exp. 2010;43:2169.

 Google Scholar

Kahlert C, Bergmann F, Beck J, Welsch T, Mogler C, Herpel E, Dutta S, Niemietz T, Koch M, Weitz J. Low expression of aldehyde dehydrogenase 1a1 (aldh1a1) is a prognostic marker for poor survival in pancreatic cancer. BMC Cancer. 2011;11:275.

 PubMed Web of Science ®Google Scholar

Kim IG, Lee JH, Kim SY, Kim JY, Cho EW. Fibulin-3 negatively regulates aldh1 via c-met suppression and increases gamma-radiation-induced sensitivity in some pancreatic cancer cell lines. Biochem Biophys Res Commun. 2014;454(3):369–375.

 PubMed Web of Science ®Google Scholar

Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, Wang H, Liu Z, Su Y, Stass SA, et al. Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res. 2009;7(3):330–338.

 PubMed Web of Science ®Google Scholar

Li X, Wan L, Geng J, Wu CL, Bai X. Aldehyde dehydrogenase 1a1 possesses stem-like properties and predicts lung cancer patient outcome. J Thorac Oncol. 2012;7(8):1235–1245.

 PubMed Web of Science ®Google Scholar

Moreb JS, Baker HV, Chang LJ, Amaya M, Lopez MC, Ostmark B, Chou W. Aldh isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells. Mol Cancer. 2008;7:87.

 PubMed Web of Science ®Google Scholar

Moreb JS, Muhoczy D, Ostmark B, Zucali JR. Rnai-mediated knockdown of aldehyde dehydrogenase class-1a1 and class-3a1 is specific and reveals that each contributes equally to the resistance against 4-hydroperoxycyclophosphamide. Cancer Chemother Pharmacol. 2007;59(1):127–136.

 PubMed Web of Science ®Google Scholar

Moreb JS, Gabr A, Vartikar GR, Gowda S, Zucali JR, Mohuczy D. Retinoic acid down-regulates aldehyde dehydrogenase and increases cytotoxicity of 4-hydroperoxycyclophosphamide and acetaldehyde. J Pharmacol Exp Ther. 2005;312(1):339–345.

 PubMed Web of Science ®Google Scholar

Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Liu H, Behrens C, Shay JW, Wistuba II, et al. Essential role of aldehyde dehydrogenase 1a3 for the maintenance of non-small cell lung cancer stem cells is associated with the stat3 pathway. Clin Cancer Res. 2014;20(15):4154–4166.

 PubMed Web of Science ®Google Scholar

Luo Y, Dallaglio K, Chen Y, Robinson WA, Robinson SE, McCarter MD, Wang J, Gonzalez R, Thompson DC, Norris DA, et al. Aldh1a isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells. 2012;30(10):2100–2113.

 PubMed Web of Science ®Google Scholar

Vasiliou V, Thompson DC, Smith C, Fujita M, Chen Y. Aldehyde dehydrogenases: from eye crystallins to metabolic disease and cancer stem cells. Chem Biol Interact. 2013;202(1–3):2–10.

 PubMed Web of Science ®Google Scholar

Clark DW, Palle K. Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets. Ann Transl Med. 2016;4(24):518–518.

 PubMed Web of Science ®Google Scholar

Li T, Su Y, Mei Y, Leng Q, Leng B, Liu Z, Stass SA, Jiang F. Aldh1a1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients’ outcome. Lab Invest. 2010;90(2):234–244.

 PubMed Web of Science ®Google Scholar

van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzman-Ramirez N, Hamdy FC, Eaton CL, Thalmann GN, Cecchini MG, et al. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 2010;70(12):5163–5173.

 PubMed Web of Science ®Google Scholar

van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Pelger RC, van der Pluijm G. The aldehyde dehydrogenase enzyme 7a1 is functionally involved in prostate cancer bone metastasis. Clin Exp Metastasis. 2011;28(7):615–625.

 PubMed Web of Science ®Google Scholar

Wu J, Mu Q, Thiviyanathan V, Annapragada A, Vigneswaran N. Cancer stem cells are enriched in fanconi anemia head and neck squamous cell carcinomas. Int J Oncol. 2014;45(6):2365–2372.

 PubMed Web of Science ®Google Scholar

Kurth I, Hein L, Mabert K, Peitzsch C, Koi L, Cojoc M, Kunz-Schughart L, Baumann M, Dubrovska A. Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma. Oncotarget. 2015;6(33):34494–34509.

 PubMedGoogle Scholar

Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, Guan XY. Aldehyde dehydrogenase discriminates the cd133 liver cancer stem cell populations. Mol Cancer Res. 2008;6(7):1146–1153.

 PubMed Web of Science ®Google Scholar

Suzuki E, Chiba T, Zen Y, Miyagi S, Tada M, Kanai F, Imazeki F, Miyazaki M, Iwama A, Yokosuka O. Aldehyde dehydrogenase 1 is associated with recurrence-free survival but not stem cell-like properties in hepatocellular carcinoma. Hepatol Res. 2012;42(11):1100–1111.

 PubMed Web of Science ®Google Scholar

Chen MH, Weng JJ, Cheng CT, Wu RC, Huang SC, Wu CE, Chung YH, Liu CY, Chang MH, Chen MH, et al. Aldh1a3, the major aldehyde dehydrogenase isoform in human cholangiocarcinoma cells, affects prognosis and gemcitabine resistance in cholangiocarcinoma patients. Clin Cancer Res. 2016;22(16):4225–4235.

 PubMed Web of Science ®Google Scholar

Xu SL, Liu S, Cui W, Shi Y, Liu Q, Duan JJ, Yu SC, Zhang X, Cui YH, Kung HF, et al. Aldehyde dehydrogenase 1a1 circumscribes high invasive glioma cells and predicts poor prognosis. Am J Cancer Res. 2015;5(4):1471–1483.

 PubMed Web of Science ®Google Scholar

Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, Luthra S, Chandran UR, Benos PV, Smith L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1a3. Proc Natl Acad Sci USA. 2013;110(21):8644–8649.

 PubMed Web of Science ®Google Scholar

Data availability and materials

The materials that support the conclusions of this review have been included within the article.