International Journal of Current Research and Review (IJCRR)

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IJCRR - Vol 11 Issue 02, January

Pages: 07-10

Date of Publication: 22-Jan-2019


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An Innovative Quinone (Pyrroloquinoline Quinone) and its Antiproliferative Effects

Author: Flores-Encarnacion, M., Cabrera-Aguilar I., Aguilar-Gutierrez G.R., Cabrera-Maldonado, C.

Category: Healthcare

Abstract:The pyrroloquinoline quinine is a cofactor discovered in bacteria. It is associated with various bacterial soluble and membrane enzymes that directly oxidize sugars, alcohols, aldehydes. In higher organisms, it has been reported that pyrroloquinoline quinine acts as a potent free radical scavenger and it seems to intervene in different processes causing remarkable benefits. One of the most important effects is that pyrroloquinoline quinine induced apoptosis in different cancer cell lines. It is interesting to observe the role of pyrroloquinoline quinine as pro-apoptotic agent. This review shows the most relevant aspects of this cofactor and its antiproliferative effects.

Keywords: Pyrroloquinoline quinone, PQQ, Cofactor, Effect, Antiproliferative

DOI URL: http://dx.doi.org/10.31782/IJCRR.2019.1122

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INTRODUCTION

PQQ is a substance of quinoid nature discovered as a cofactor in different bacterial genera (Amador-Bravo, 2016; Ameyama et al., 1991; Choi et al., 2008; Misra et al., 2012). As a cofactor, it catalyzes the oxidation of organic compounds such as monosaccharides, alcohols and short chain aldehydes. It has been reported that PQQ is linked covalently and non-covalently to enzymes (Attwood et al., 1991; Flores-Encarnación et al., 2004; Goodwin and Anthony, 1998; Matsushita et al., 2002; Naveed et al., 2016). Due to its quinoid nature, PQQ has very active carbonyl groups, being a powerful antioxidant agent. It has been observed that the presence of PQQ in certain bacterial genera facilitates the activation of alternative metabolic pathways for the utilization of sugars; it also favors the production of high quantities of acidic substances in the external environment of bacteria by direct oxidation of sugars or alcohols (Choi et al., 2008). PQQ is a novel quinone of bacterial origin that has changed the vision regarding diseases such as cancer because PQQ has been proposed as a possible alternative for the treatment of this disease, according to results obtained in different cell lines.

In recent years, the benefits of PQQ have been demonstrated when this substance is administered in plants or diet of different experimental animals(Amador-Bravo et al., 2016; Bauerly et al., 2011; Choi et al., 2008; Flores-Encarnación et al., 2014; Harris et al., 2013; Misra et al., 2012; Oteino et al., 2015). For example, it has a been attributed to PQQ the promotion of growth factors in tomato plantations, increasing amount of macronutrients and number of fruits. In rats, the use of a diet supplemented with PQQ showed a significant change in the learning (Amador-Bravo et al., 2016; Fukui et al., 2001; Harris et al., 2013; Ohwada et al., 2008). It has been reported that PQQ acts as a potent free radical scavenger; it suppresses the production of superoxide radicals(Hamagishi et al., 1988; Matsumoto et al., 1988; Zhang et al., 2013). PQQ has been described as a new vitamin and it seems to intervene in different processes in higher organisms causing remarkable benefits(McIntire, 1998). In recent years, the effect of PQQ on different cancer cell lines has been studied and it has been observed that PQQ induces apoptosis (Min et al., 2014). This review shows the most relevant aspects of PQQ and its antiproliferative effects.

PQQ

PQQ is a soluble anionic compound of low molecular weight, which has been classified as a new vitamin and as an essential nutrient, since it has been proven that it plays important roles: in cell proliferation, it is an antioxidant of lipid peroxidation and its beneficial effects have also been observed in cellular lesions (Shui et al., 2015; Azizi et al., 2014). PQQ is a nutrient that is well distributed in nature and serves as a non-covalent cofactor of redox reactions in certain bacterial dehydrogenase (named quinoproteins) (Flores-Encarnación et al., 2004; Matsushita et al., 2002; Tao et al., 2007). PQQ is not synthesized in mammals, however it has been found in several levels of concentration in plants, in certain foods, such as kiwi, egg, wine, even in human breast milk (Noji et al., 2007). It has been found that PQQ develops many important functions in humans and animals, including roles in nutrition, protection of the heart by ischemia, preventing damage to the liver by alcohol, sequestering free radicals from the body, increasing the level of nerve growth factor (in astrocytes) and inhibiting melanin production in melanoma cells (Fukui et al., 2001; Wang et al., 2014).

PQQ as a vitamin

PQQ has been proposed as a new vitamin because it had beneficial effects on healthy cells at low concentrations (nanomolar to micromolar order) (Chowanadisai et al., 2010; Steinberg et al., 2003). It is known that glutamate is the free amino acid more abundant in the central nervous system but excess glutamate can affect progenitor cells and induces apoptosis in neural trunkand other cells(Pavlovic et al., 2006). However, in vitro studies have shown that when the cells were cultured at different PQQ concentrations (3 nM to 30 mM), it was observed that PQQ favored cell proliferation and significantly attenuated cell damage induced by glutamate (Shui et al., 2015). On the other hand, it is known that vitamins perform their function in team and in certain specific places of the body. Some authors have studied the effect of PQQ and vitamin E in peripheral nerves such as sciatica. They discovered that PQQ together with vitamin E favored the fastest recovery from nerve damage (increasing the regeneration of axons). Therefore, those two agents were been proposed for an effective regeneration in peripheral nerve lesions (Azizi et al., 2014; Naveedet al., 2016).Tao et al., (2007) proposed to PQQ as a cardioprotective agent after observing a remarkable reduction of peroxides treating adult rat myocardium cells with H2O2 and PQQ.

PQQ as growth promoter

This novel quinone was proposed as a potent growth factor in mice and as a promoter of DNA synthesis in human fibroblasts(Amador-Bravo et al., 2016;Chowanadisai et al., 2010;Harris et al., 2013; Misra et al., 2012). Kumazawa et al., (2007) observed in NIH3T3mouse fibroblasts that PQQ increased cell proliferation through of signals related to Rats and it was observed that effect of PQQ derived from regulation of nitric oxide (NO) levels. Those studies contributed to expand understanding of cellular mechanisms, cell signaling and gene expression relevant to PQQ in mammals (Kumazawa et al., 2007).

On the other hand, it has been reported that coenzymes such as PQQ showed a stimulating effect on the synthesis of nerve growth factor in mouse fibroblasts and BALBc/3T3 cell line, concluding that PQQ plays a important role in neuronal survival (Azizi et al., 2014; Misra et al., 2012; Murase et al., 1993). The effect of PQQ has also been studied in fibroblasts, myocytes and mouse brainmicrovascular endothelial cells, where it was observed that PQQ in nanomolar concentrations protected these cells from high glucose-induced damage, thus reducing apoptosis and increasing the number of mitochondria in the cells. Apparently the protective effect was due to intracellular expression of hypoxia-inducible factor 1 alpha subunit (HIF-1α) (Wang et al., 2014). It is known that liver fibrosis develops when there is chronic inflammation and destruction of liver cells, however it has been observed that PQQ has a suppressive, anti-oxidant and anti-fibrogenic effect. It has been reported that PQQ exerted a potent anti-fibrotic activity and reactive oxygen species (ROS) scavenging activity in Balb/C mouse models of liver fibrosis (Jia et al., 2015). In the majority of the studies that have been carried out, the effect of PQQ in nanomolar concentration has been tested, however in the last years other studies have been developed in different cell lines of malignant cells, showing that in micromolar quantities PQQ has apoptotic effects (Min et al., 2014).

The antiproliferative effects of PQQ

It has been reported that the murine melanoma cell line B16F1is characterized because melanocytes produce a large amount of tyrosinase enzyme. Tyrosinase is a key enzyme in melanin synthesis and that in high amounts produces hyperpigmentation of the skin and even cancer (melanoma) (Sato et al., 2008).Sato and Toriyama (2009) reported that PQQ between 12.5 to 25 μM inhibited the synthesis of mRNA that codes for tyrosinase involved in the production of melanin. These authors observed a decrease in cell proliferation and melanin production. Although the mechanism of action is still unknown, it has been proposed PQQ as a possible treatment against melanogenesis and hyperpigmentation disorders. In cell lines A-549 (adenocarcinoma of human lung), Neuro-2A (mouse neuroblastoma) and HCC-LM3 (human hepatocellular carcinoma), it has been observed that PQQ at concentrations 30 to 75 μM suppressed cell proliferation by inducing apoptosis. In addition, it was observed that PQQ increased the activity of caspase-3, produced cell cycle arrest in G0/G1 phase and produced the intracellular accumulation of reactive oxygen species (ROS) and the decline of ATP levels (Min et al., 2014). In the cell line A431 (human squamous cell carcinoma), it has been observed that PQQ at concentrations in the nanomolar order, promoted cell proliferation increasing growth up to 180%, however at concentrations in the micromolar order PQQ induced apoptosis (Kimura et al., 2012). In the cell line U937 (human promonocitic leukemia), it was reported that PQQ at concentrations of 50-100 μM induced a depletion of glutathione and, consequently, an increase in reactive oxygen species (ROS). The decrease in glutathione led to the cells suffering necrosis, indicating that PQQ increased cytotoxicity due to the change in the cellular redox state. Thus, glutathione depletion can change the mode of cell death to necrosis in the presence of PQQ. The modulation of intracellular glutathione could be a strategy to enhance the cytotoxicity of PQQ (Nunone et al., 2008; Shankar et al., 2013). As a scavenger of reactive oxygen species, PQQ appears to be a potent neuroprotector (Scanlon et al., 1997). Zhang et al. (2009 ) reported that the addition of 1 to 20 μM of PQQ in the human neuroblastoma cell line SH-SY5Y, together with the beta-amyloid protein (Aβ), prevents the damage caused by the latter, thus avoiding apotosis. Beta-amyloid proteins have been proposed as one of the causes of Alzheimer's disease that produces neurotoxicity (increasing the production of reactive oxygen species) and induces apoptosis of neurons (Zhang et al. (2013). The alpha-synuclein (α-syn) is a small soluble protein expressed primarily at presynaptic terminals in the central nervous system and it is related to several neurodegenerative diseases, including Parkinson’s disease (Amador-Bravo et al., 2016). The recent data suggest that α-syn has a role in regulating membrane stability and neuronal plasticity (Overk et al., 2014). When the α-syn is mutated the function is lostcausing the formation of bodies of Lewis, cytotoxicity, apoptosis in neurons of the substantia nigra and therefore Parkinson’s disease (Kim et al., 2010; Kobayashi et al., 2010;Overk et al., 2014; Recchia et al., 2004). On the other hand, the rotenone is a substance that has been used as a natural pesticide. Its use has increased in recent years. However, rotenone can cross the brain barrier by penetrating the cell membrane and acting as a potent inhibitor of mitochondrial complex I leading to cell death. It has been tested in several cellular models that PQQ added to different concentrations in the presence of rotenone, protects the cells from damage and delays their harmful effects (Qin et al., 2015).

CONCLUSION

PQQ is a novel cofactor that can act as a vitamin in nanomolar concentrations; at higher concentrations PQQ could be used for the treatment of certain diseases. PQQ can induce apoptosis in cancer cells, it is also protective of neurons, of myocardium and stimulates the cognitive system, among other things. However, PQQ can also have pro-oxidant characteristics and by binding to certain compounds can exacerbate cell toxicity.

ACKNOWLEDGEMENTS

Thank to PRODEP and Facultad de Medicina-BUAP for the facilities provided for the development of this work.

CONFLICT OF INTEREST

Authors have no conflict of interest.

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