**1.2. Aldehyde dehydrogenases**

4 Dehydrogenases

reason, the subpopulation of cancer SCs (CSCs) can present a therapeutic target for poorprognostic, treatment-resistant and recurrent breast cancer. Through its role in oxidizing retinol to RA, which is a modulator of cell proliferation, ALDH1 might have a role in early

There are several isoforms of ALDH (ALDH1A1, ALDH1A2, ALDH1A3 and ALDH8A1) that play a role in RA formation by oxidation of all-trans-retinal and 9-cis-retinal in RA cell signaling, which has been related to the "stemness" characteristics of SCs (Marcato*, et al.*, 2011). ALDH1 is better as a marker of breast cancer SCs than CD44+/CD24- (Tanei*, et al.*, 2009). While cellular markers including CD133 have been used to identify tumor SCs, especially for glioblastomas (GBMs) ALDH1 was desrcribed as a marker for the identification of non-neoplastic SCs and tumor stem cells (TSCs) (Corti*, et al.*, 2006,

After CD133- GBMs are characterized to behave as brain TSCs(Beier*, et al.*, 2007). ALDH1 has also been described as a stem cell marker in various solid neoplasms including lung cancer (Jiang*, et al.*, 2009), breast carcinoma (Ginestier*, et al.*, 2007), colorectal cancer (Huang*, et al.*, 2009), and GBM. ALDH1B1 and ALDH1A1 are differentially expressed in normal human tissues. ALDH1B1 is expressed at higher levels than ALDH1A1 in human epithelial cancers. ALDH1B1 was abundantly expressed in adenocarcinomas originating from the

ALDHbr cells can be detected with ALDEFLUOR reagent by using flow cytometry or fluorescent microscopy. Aldefluor assay is based on the conversion of fluorescent non-toxic substrate for ALDH substrate to the fluorescent reaction product. Non-toxic substrate for ALDH can freely diffuse into intact, viable cells. The BODIPY aminoacetaldehyde is converted to the fluorescent product BODIPY aminoacetate by ALDH activity. These cell populations, which are known as ALDH bright (ALDHbr) cells are isolated from adult tissues by flow sorting. ALDHbr cells were also found in various cancer tissues including breast, liver, colon, pancreas, prostate, lung, ovarian and acute myelogenous leukemia and

ALDHbr population may play an important role in regenerative medicine. The regenerative potential of ALDHbr cells obtained from different tissues was investigated in various disease models such as ischemic tissue damage, hind limb model, brain damage (spinal motor

Thus, as mentioned above, ALDH is an important enzyme for cancer and stem cells. This chapter aims to represent the important role of aldehyde dehydrogenases in stem cells,

Aldehydes are formed in various physiological processes such as catabolism of transmitters like GABA, serotonin, adrenaline, noradrenaline and dopamine, as well as catabolism of amino acids. In addition, there are more than 200 different aldehydes that are produced

differentiation of SCs and stem cell proliferation (Mieog*, et al.*, 2012).

tissue and particularly in colonic adenocarcinoma (Chen*, et al.*, 2011).

are related to cancer chemo resistance (Siclari & Qin, 2010).

cancer stem cells, therapy and regenerative medicine.

atrophy, etc.) and pancreatitis.

**1.1. Aldehydes** 

Ginestier*, et al.*, 2007, Huang*, et al.*, 2009).

Aldehyde dehydrogenases [EC 1.2.1.3; *systematic name*: aldehyde: NAD(P)+oxidoreductase] catalyze aldehyde conversion into their matching acids by NAD(P)+-dependent nearly irreversible reaction. In 1949, mammalian ALDH was first discovered in ox liver. After that, many types of ALDH were distinguished according to their physico-chemical characteristics, enzymological properties, subcellular localization, and tissue distribution (Oraldi*, et al.*, 2011). They are involved in several cell functions such as proliferation, differentiation, survival as well as cellular response to oxidative stress (Jackson*, et al.*, 2011). ALDHs are commonly delivered from bacteria and humans (Moreb, 2008). Based on their physico-chemical characteristics, subcellular localization, tissue distribution and enzymological properties, a number of types of ALDH have been distinguished since the 1960s, around the time when mammalian ALDH activity was observed in ox for the first time. In 1985, 2 ALDH genes were cloned and characterized. Genes or cDNAs for more than 50 animals, fungi and bacterial ALDHs in addition to protein sequences have been discovered (Yoshida*, et al.*, 1998).

The human genome contains 19 ALDH functional genes and 3 pseudogenes (Black*, et al.*, 2009). At least 5 ALDH isozymes function in the mitochondria, and all the ALDH genes are encoded in the nucleus (Chen*, et al.*, 2010).

All of the ALDH gene superfamily plays an important role in the enzymic detoxification of endogenous and exogenous aldehydes. They are also involved in the formation of molecules that are important in cellular processes like RA, betaine and gamma aminobutyric acid

formation. Furthermore, ALDHs also have several non-enzymic functions such as binding to some hormones and other small molecules and decreasing the effects of ultraviolet irradiation in the cornea (Pappa*, et al.*, 2003, Wymore*, et al.*, 2004). The most important role of ALDHs is detoxication of aldehydes, which caused cytotoxicity, mutagenicity, genotoxicity, and carcinogenesis in healthy cells. Mutations in ALDH genes cause severe diseases including Sjögren-Larsson syndrome, pyridoxine-dependent seizures, and type II hyperprolinemia, and also plays a role in cancer and Alzheimer's disease (Black*, et al.*, 2009).

Aldehyde Dehydrogenase: Cancer and Stem Cells 7

from human embryos and grow the cells in the laboratory, and these cells are called human

In 2006, genetically "reprogrammed" stem-cell-like cells were identified by using specialized adult cells. This new type of stem cell is called **induced pluripotent SCs (iPSCs)** (Krishna*, et* 

Cancer is a class of diseases characterized by unregulated cell growth(Deisboeck*, et al.*, 2011). Cancer initiation depends on genetic mutations in series that affects cellular programming. Many cancer researches have focused on the identification and characterization of these genetic and molecular properties of cancer cells (Balmain*, et al.*, 2003). Tumors are also heterogeneous cellular entities whose growth is dependent upon dynamic interactions among the cancer cells themselves, and between cells and the constantly changing microenvironment (Bissell & Radisky, 2001). That kind of interaction is depent on signaling through cell adhesion molecules and different cell responses to growth factors and other external signals. All of these interactive processes act together to control cell phenotypic behaviors such as proliferation, apoptosis, and migration. There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected

According to recent statistics, cancer accounts for about 23% of the total deaths in the USA

Cancer is caused by many internal and external factors. Inherited mutations, hormones, and immune conditions are internal factors while tobacco, diet, radiation, and infectious organisms are environmental/acquired factors (Kalluri & Weinberg, 2009, Nagy*, et al.*, 2010, Langley & Fidler, 2011, Mantel & Schmidt-Weber, 2011, Noman*, et al.*, 2011). In recent years, a particular sub-population of tumor cells are said to have a critical role in cancer; these cells are commonly called **CSCs** or **tumor initiating cells (TICs).** In most cancer types, CScs have been identified. CSCs are characterised by their two important properties: (1) Enhanced tumorigenicity; and (2) the capacity for selfrenewal/differentiation (Bonnet & Dick, 1997, Al-Hajj*, et al.*, 2003). Thus, isolating CSCs is important in analyzing their characteristics *in vitro*. The isolated CSC population will not only give rise to de novo tumors with high efficiency, but will also recapitulate the tumor

One potential human CSC marker is the membrane antigen CD133 (Prominin) identified in subpopulations of cells in brain, colon and lung tumors (Singh*, et al.*, 2004, Ricci-Vitiani*, et al.*, 2007, Eramo*, et al.*, 2008). CD133+ tumor cells are also a marker identifying lung CSCs

The expression and activity of ALDHs is determined as another potential CSC marker (Ginestier*, et al.*, 2007). ALDH1 is a marker of normal and malignant human mammary SCs and a predictor of poor clinical outcome (Huang*, et al.*, 2009). Aldehyde dehydrogenase

and is the second most common cause of death after heart disease (Jemal*, et al.*, 2007).

embryonic SCs.

**2.1. Cancer stem cells** 

(Lakshmi Prasanna & Sathish Kumar, 2011).

with both CSC and non-CSC populations.

(Wang*, et al.*, 2008, Salnikov*, et al.*, 2010).

*al.*, 2011).

Functions of some of these ALDHs in endobiotic and xenobiotic metabolisms have been highly reviewed before and the distinctive metabolic pathways' influences have been depicted. Because of their chemical reactivity, many distinct aldehydes are pervasive in nature and are toxic at low levels. Hence, levels of metabolic-intermediate aldehydes should be cautiously regulated. The presence of several distinct ALDH families in most studied organisms seem to have wide fundamental tissue distribution. A wide range of allelic variants within the ALDH gene family have been identified, leading to heterogeneity in pharmacogenetic characteristics between individuals, resulting distinctive phenotypes including intolerance to alcohol and increased risk of ethanol-induced cancers in most cases (ALDH2 and ALDH1A1), Sjogren-Larson Syndrome (ALDH3A1), type II hyperprolinemia (ALDH4A1), 4-hydroxybutyric aciduria, mental retardation and seizures (ALDH5A1), developmental delay (ALDH6A1), hyperammonemia (ALDH18A1), Pyridoxine-dependent epilepsy (ALDH7A1), and late-onset Alzheimer's disease (ALDH2).

ALDH dysfunction could also be caused by drugs and environmental substances, substrate inhibition, as well as oxidative and metabolic stress. ALDH activity in drug resistance to oxazaphosphorines is one of the most vigorously studied pathways. The role of ALDH1A1 in drug resistance has been studied first in hematopoietic progenitors and more recently in lung cancer (Marchitti*, et al.*, 2008).
