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Home > Expression of Circadian Clock and Cell Cycle Genes in Chronic Lymphocytic Leukemia

Expression of Circadian Clock and Cell Cycle Genes in Chronic Lymphocytic Leukemia

Thesis Info

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Author

Rana, Sobia

Program

PhD

Institute

University of Health Sciences

City

Lahore

Province

Punjab

Country

Pakistan

Thesis Completing Year

2012

Thesis Completion Status

Completed

Subject

Natural Sciences

Language

English

Link

http://prr.hec.gov.pk/jspui/handle/123456789/1397

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726170355

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Circadian rhythms are endogenous, self-sustained oscillations of multiple biological processes with approximately 24-hr rhythmicity. Circadian genes and their protein products constitute the molecular components of the circadian oscillator that form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) that include various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. The current study was carried out to gain further insights into the roles of circadian genes and their downstream targets (cell cycle genes) in chronic lymphocytic leukemia (CLL). We analyzed peripheral blood from 37 CLL patients and equal number of their age- and sex-matched healthy controls for the expression of the four circadian clock and three cell cycle genes. The expression levels of BMAL1, PER1, PER2,MYC, CYCLIN D1 and WEE1 were significantly impaired in CLL cases compared with those in healthy individuals (P < 0.001). BMAL1, PER1, PER2 and WEE1 were found down regulated whereas MYC and CYCLIN D1 were found upregulated. This implies that the deregulated expression of circadian clock genes through their influence on downstream clock-controlled cell cycle genes can play a role in the manifestation of CLL. Moreover, when expression levels of abovementioned genes were compared between shift workers and non-shift workers within the CLL group, the expression levels were more aberrant in shiftworkers compared to non-shift workers. This indicates that circadian dysregulation in terms of shift work may also be a contributing factor in the etiology of CLL. In the current study, serum melatonin levels were also determined in 37 CLL cases and their healthy controls. Serum melatonin levels were found significantly low (P<0.05) in CLL subjects as compared to healthy controls. Furthermore, melatonin levels were found still lower in shift workers as compared to non-shift workers within CLL group. Our results suggest that down regulation of BMAL1, PER1 and PER2 is related to upregulation of Cyclin D1, MYC and down regulation of WEE1 in CLL. Thus, aberrant expression of clock genes can lead to abnormal expression of downstream cell-cycle genes and play a role in the manifestation of CLL. Moreover, low melatonin levels in CLL patients may play a part in xivderegulation of circadian clock gene expression and shiftwork serves as a further contributing factor to an already perturbed circadian clock genes’ expression and low melatonin levels in CLL.
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Identification and Characterization of Pharmacological Inhibitors of Alkaline Phosphatase Isozymes & Nucleotide Pyrophosphatase Isozymes

Ecto–nucleotidases are nucleotide metabolizing enzymes that are categorized into four different families; Alkaline Phosphatases (APs), Nucleotide Pyrophosphatase/phosphodiesterases (NPPs), Nucleoside Triphosphate Diphosphohydrolases (NTPDases) and Ecto–5′–Nucleotidase (e5′NT). These enzymes are responsible for the hydrolysis of extracellular nucleotides, i.e., adenosine–5′–triphosphate (ATP), adenosine–5′–diphosphate (ADP), adenosine–5′– monophosphate (AMP), uridine–5′–triphosphate (UTP) and uridine–5΄–diphosphate (UDP) into nucleosides, i.e., ADP, AMP, UDP, UMP and adenosine, respectively. The structural and functional role of these ecto–nucleotidases in purinergic signaling varies considerably between enzyme classes. Each member possesses different enzymatic and cellular expression properties. Among the different ecto–nucleotidase families, APs and NPPs synergize and overlap in their functions, particularly during skeletal mineralization. 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Therefore, potent and selective inhibitors of h-TNAP and h-NPP1 might be useful candidates for the treatment or prevention of some diseases. In this study, different derivatives of amides, chromones, quinolones and pyrazoles were tested for their potential to inhibit membrane–bound isozymes. The obtained results suggested that amide derivatives 3b, 4d, 2b (diarylsulphonamides), 4i, 4f, 4b (1H–pyrazol–4–yl benzamides), 2i, 2e and 2a (thiazol–2–ylidene–benzamides) were found highly potent inhibitors of h-TNAP Among the tested compounds, 3b, 4i and 2e showed the maximum inhibitory potential with an IC50 values of 0.21 ± 0.02, 0.34 ± 0.08 and 0.079 ± 0.002 µM, respectively. In the chromone derivatives, 1f, 1d, 1c (3,3′– carbonyl–bis(chromones), 7c, 7h, 7i (3–(5–(benzylideneamino)thiozol–3–yl)–2H– chromen–2–ones), 10a and 10g (triazolothiadiazin–3–yl 2–H–chromone) were found potent inhibitors of h-TNAP. Among the chromone derivatives 1d, 7h and 10a exhibited maximum inhibition with an IC50 values of (IC50±SEM) 2.47 ± 0.03, 0.21 ± 0.04 and 0.31 ± 0.09 µM, respectively. From the quinolone and quinoline derivatives, 3j, 3b (quinoline–4–carboxylic acid), 3a, 2b and 5a (4–quinolone) were found to be potent inhibitors against h-TNAP and among these compound 3j and 2b showed maximum inhibitory potential with an IC50±SEM values of 0.11 ± 0.07 and 1.34 ± 0.11 µM, respectively. The isoquinoline derivatives; 4p, 4l and 4i were identified as potent inhibitors of NPPs, where 4i was found to be the most potent inhibitor with an IC50 value of 0.11 ± 0.01 µM. The last group of compounds, i.e., Pyrazoles derivatives, 6i, 6e, 5e (2–arylated thiadiazolopyrimidones) were identified as the selective inhibitors of NPPs, and the most potent derivative was 6e (IC50±SEM= 0.31±0.01 µM). Compounds 4i, 4m and 4n (5–perfluoroalkylpyrazoles) were found as the selective inhibitors of APs with 4i (IC50±SEM= 0.45±0.01 µM) as the most potent inhibitor of the series. Compound 6a and 6b (pyrazole pyrimidones) were identified as the dual inhibitors of both APs and h-NPP-1. Kinetics experiments of the most potent derivatives were carried out to find the mechanism of inhibition on the respective isozyme by these derivatives. To determine the plausible binding modes and binding energies, docking studies were performed that supported the in–vitro inhibitory activity of potent and selective inhibitors. The cytotoxic results obtained from MTT assay confirmed that the selected compounds library had anticancer potential against MCF–7, K–562 and HeLa cell lines in comparison to normal cell line, i.e., BHK–21. Compounds 3b (diarylsulphonamides), 4i (1H–pyrazol–4–yl benzamides), 2i (thiazol–2–ylidene–benzamides), 1f (3,3′–carbonyl–bis(chromones), 7c (thiozol–3–yl–2H–chromen–2–ones), 10a (triazolothiadiazin–3–yl 2H–chromen– 2–ones), 4p (isoquinolones), 3j (quinoline–4–carboxylic acid), 3a (4–quinolone), 6i (2–arylated thiadiazolopyrimidones), 4i (5–perfluoroalkylpyrazoles) and 6b (pyrazole pyrimidones) induced maximum growth inhibition of MCF–7 cells and exhibited GI50 values 5.75 ± 0.12, 8.59 ± 0.16, 4.16 ± 0.17, 10.2± 1.07, 8.99 ± 1.24, 8.51 ± 0.62, 8.21 ± 0.31, 5.49 ± 0.32, 10.4 ± 2.05, 5.61 ± 0.72, 5.52 ± 0.92, 5.65 ± 0.75 and 13.5 ± 1.03 µM, respectively. Compounds 4d (diarylsulphonamides), 4f (1H–pyrazol–4–yl benzamides), 2e (thiazol–2–ylidene–benzamides), 1d (3,3′–carbonyl–bis(chromones), 7h (thiozol–3–yl–2H–chromen–2–ones), 10a (triazolothiadiazin–3–yl 2–H– chromone), 4l (isoquinolones), 3j (quinoline–4–carboxylic acid), 2b (4–quinolone), 6e (2–arylated thiadiazolopyrimidones), 4m (5–perfluoroalkylpyrazoles) and 6a (pyrazole pyrimidones) induced maximum growth inhibition of K–562 cells and exhibited GI50 values: 12.2 ± 1.09, 7.27 ± 0.48, 5.86 ± 0.15, 5.53 ± 0.35, 25.4 ± 1.09, 8.37 ± 0.14, 10.9 ± 1.04, 25.8 ± 2.79, 7.91 ± 0.92, 16.3 ± 1.25, 22.4 ± 1.88 and 16.6 ± 0.04 µM. Compounds 2b (diarylsulphonamides), 4b (1H–pyrazol–4–yl benzamides), 2a (thiazol–2–ylidene–benzamides), 1c (3,3′–carbonyl–bis(chromones), 7i (thiozol– 3–yl–2H–chromen–2–ones), 10g (triazolothiadiazin–3–yl 2H–chromen–2–ones), 4i (isoquinolones), 3b (quinoline–4–carboxylic acid), 2b (4–quinolone), 5e (2–arylated thiadiazolopyrimidones), 4n (5–perfluoroalkylpyrazoles) and 6c (pyrazole pyrimidones) caused significant growth inhibition of HeLa cells and exhibited GI50 values: 4.64 ± 0.34, 8.22± 0.78, 11.5 ± 0.15, 10.1 ± 0.73, 8.37 ± 0.45, 12.9 ± 0.13, 14.3 ± 1.26, 11.5 ± 1.05, 7.65 ± 0.97, 6.13 ± 0.92, 5.79 ± 0.56 and 12.4 ± 0.94 µM, respectively. Cell cycle arrest and apoptosis was confirmed by following the estimation of apoptosis by fluorescence microscopy using two nucleus staining dyes, i.e., DAPI and PI. The compounds exhibiting maximum anticancer potential also induced maximum apoptosis in the respective cell lines. Moreover, the obtained results suggested that untreated cells exhibited the homogenous staining of the nuclei, while the cells treated with different derivatives exhibited nuclear condensation and cell shrinkage along with the membrane blebbing which showed that the treated compounds have induced the cell death of respective cell lines. Furthermore, the mechanism of cytotoxic compound was determined by DNA interaction studies and it was found that the most potent inhibitors exhibited the non–covalent mode of interaction with the herring sperm–DNA (HS–DNA). The mechanism of action of the cytotoxic derivatives against MCF–7 cells suggested that the compound 3b (diarylsulphonamides), 1f (3,3′–carbonyl–bis(chromones), 3a (4–quinolone) and 6i (2–arylated thiadiazolopyrimidones) exhibited maximum inhibitory potential towards MCF–7, also depicted higher DNA interactions having Gibbs free energy Δ–17.48, Δ–17.50, Δ–18.19 and Δ–17.51 KJ/mol. Against the K–562 cells , compounds 4f (1H–pyrazol–4–yl benzamides), 1d (3,3′–carbonyl–bis(chromones), 2b (4–quinolone) and 6a (pyrazole pyrimidones) showed the maximum DNA interactions having Gibbs free energy Δ–17.88, Δ–17.86, Δ–18.09 and Δ–18.31 KJ/mol, respectively. Similarly, against HeLa, 4b (1H–pyrazol–4–yl benzamides), 10g (triazolothiadiazin–3–yl 2H– chromen–2–ones) and 3b (quinoline–4–carboxylic acid) exhibited maximum DNA interactions with Gibbs free energy Δ–17.21, Δ–18.36 and Δ–18.20 KJ/mol, respectively. Results obtained through the present studies revealed that the many of the compounds were potent and selective inhibitors of APs and NPPs with strong anticancer potential can be used as potential leads to synthesize more derivatives that can be beneficial for the treatment of health disorders associated with the over-expression of APs and NPPs. It was further concluded that due to strong inhibitory potential and lower effective concentration against enzymes and cancer cell lines these compounds must be further exploited to explore molecular basis of underlying anticancer mechanisms through in vivo studies for pharmaceutical point of view. Knowledge thus generated will be helpful for the development of future novel drugs." xml:lang="en_US