Epidemiological studies indicate that treatment with metformin, an AMP-activated protein kinase (AMPK) activator, reduces the incidence of cancers. Activation of AMPK has also been reported to oppose tumor progression in diverse types of cancers and offers promising cancer therapy. Furthermore, AMPK is a primary regulator of energy metabolism and has also been implicated in cell cycle progression, angiogenesis, cell transformation, migration, and cancer. We have recently synthesized novel flavonoids, namely, triphenylmethanol derivatives (TPMs), but the effectiveness of the TPMs on the activity of AMPK remains unclear. We hypothesized that the novel TPMs would inhibit cancer cell proliferation through the activation of AMPK isoforms in cells. The effects of TPMs on prostate cells (PC-3) were investigated. Cells were exposed to TPMs for either 12 or 24 hr. at the respective doses of 0, 25, 50 100, and 200 μM based on the cell viability studies by the (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) (MTT) assay. The results indicate that cells exposed to the respective doses of TPMs increased both phospho- and total-AMPKα1 in a dose- and time-dependent manner. The effects of the increases for the phospho- and total-AMPKα in cells were greater for the 24-hr than the 12-hr. incubation. Further studies are currently going on to elucidate the specificities of the said insults in increasing the phospho- and total-AMPKα activities and for the other respective isoforms.
References
[1]
Hardie, D.G., Ross, F.A. and Hawley, S.A. (2012) AMPK: A Nutrient and Energy Sensor That Maintains Energy Homeostasis. Nature Reviews Molecular Cell Biology, 13, 251-262. https://doi.org/10.1038/nrm3311
[2]
Hardie, D.G. (2014) AMPK—Sensing Energy While Talking to Other Signaling Pathways. Cell Metabolism, 20, 939-952. https://doi.org/10.1016/j.cmet.2014.09.013
[3]
Haurie, V., Boucherie, H. and Sagliocco, F. (2003) The Snf1 Protein Kinase Controls the Induction of Genes of the Iron Uptake Pathway at the Diauxic Shift in Saccharomyces cerevisiae. Journal of Biological Chemistry, 278, 45391-45396. https://doi.org/10.1074/jbc.m307447200
[4]
Hardie, D.G. and Hawley, S.A. (2001) AMP-Activated Protein Kinase: The Energy Charge Hypothesis Revisited. BioEssays, 23, 1112-1119. https://doi.org/10.1002/bies.10009
[5]
Hawley, S.A., Davison, M., Woods, A., Davies, S.P., Beri, R.K., Carling, D., et al. (1996) Characterization of the AMP-Activated Protein Kinase Kinase from Rat Liver and Identification of Threonine 172 as the Major Site at Which It Phosphorylates AMP-Activated Protein Kinase. Journal of Biological Chemistry, 271, 27879-27887. https://doi.org/10.1074/jbc.271.44.27879
[6]
Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.J., Udd, L., Mäkelä, T.P., et al. (2003) Complexes between the LKB1 Tumor Suppressor, STRADα/β and MO25α/β Are Upstream Kinases in the AMP-Activated Protein Kinase Cascade. Journal of Biology, 2, Article No. 28. https://doi.org/10.1186/1475-4924-2-28
[7]
Hemminki, A., Markie, D., Tomlinson, I., Avizienyte, E., Roth, S., Loukola, A., et al. (1998) A Serine/Threonine Kinase Gene Defective in Peutz-Jeghers Syndrome. Nature, 391, 184-187. https://doi.org/10.1038/34432
[8]
Jenne, D.E., Reomann, H., Nezu, J., Friedel, W., Loff., S., Jeschke, R., et al. (1998) Peutz-Jeghers Syndrome Is Caused by Mutations in a Novel Serine Threoninekinase. Nature Genetics, 18, 38-43. https://doi.org/10.1038/ng0198-38
[9]
Imran, M., Rauf, A., Abu-Izneid, T., Nadeem, M., Shariati, M.A., Khan, I.A., et al. (2019) Luteolin, a Flavonoid, as an Anticancer Agent: A Review. Biomedicine & Pharmacotherapy, 112, Article ID: 108612. https://doi.org/10.1016/j.biopha.2019.108612
[10]
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A. and Jemal, A. (2018) Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 68, 394-424. https://doi.org/10.3322/caac.21492
[11]
Theodoratou, E., Timofeeva, M., Li, X., Meng, X. and Ioannidis, J.P.A. (2017) Nature, Nurture, and Cancer Risks: Genetic and Nutritional Contributions to Cancer. Annual Review of Nutrition, 37, 293-320. https://doi.org/10.1146/annurev-nutr-071715-051004
[12]
Afshin, A., Sur, P.J., Fay, K.A., Cornaby, L., Ferrara, G., Salama, J.S., Mullany, E.C., Abate, K.H., Abbafati, C., Abebe, Z., et al. (2019) Health Effects of Dietary Risks in 195 Countries, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet, 393, 1958-1972.
[13]
Darband, S.G., Kaviani, M., Yousefi, B., Sadighparvar, S., Pakdel, F.G., Attari, J.A., et al. (2018) Quercetin: A Functional Dietary Flavonoid with Potential Chemo-Preventive Properties in Colorectal Cancer. Journal of Cellular Physiology, 233, 6544-6560. https://doi.org/10.1002/jcp.26595
[14]
Giovannucci, E. (2018) Nutritional Epidemiology and Cancer: A Tale of Two Cities. Cancer Causes & Control, 29, 1007-1014. https://doi.org/10.1007/s10552-018-1088-y
[15]
Xu, D., Li, Y., Meng, X., Zhou, T., Zhou, Y., Zheng, J., et al. (2017) Natural Antioxidants in Foods and Medicinal Plants: Extraction, Assessment and Resources. International Journal of Molecular Sciences, 18, Article 96. https://doi.org/10.3390/ijms18010096
[16]
Shashirekha, M.N., Mallikarjuna, S.E. and Rajarathnam, S. (2013) Status of Bioactive Compounds in Foods, with Focus on Fruits and Vegetables. Critical Reviews in Food Science and Nutrition, 55, 1324-1339. https://doi.org/10.1080/10408398.2012.692736
[17]
Nabavi, S.M., Samec, D., Tomczyk, M., Milella, L., Russo, D., Habtemariam, S., Suntar, I., Rastrelli, L., Daglia, M., Xiao, J., et al. (2018) Flavonoid Biosynthetic Pathways in Plants: Versatile Targets for Metabolic Engineering. Biotechnology Advances, 38, Article ID: 107316.
[18]
Liu, J., Wang, X., Yong, H., Kan, J. and Jin, C. (2018) Recent Advances in Flavonoid-Grafted Polysaccharides: Synthesis, Structural Characterization, Bioactivities and Potential Applications. International Journal of Biological Macromolecules, 116, 1011-1025. https://doi.org/10.1016/j.ijbiomac.2018.05.149
[19]
Chen, H., Lin, P., Shih, Y., Wang, K., Hong, Y., Shieh, T., et al. (2019) Natural Antioxidant Resveratrol Suppresses Uterine Fibroid Cell Growth and Extracellular Matrix Formation in Vitro and in Vivo. Antioxidants, 8, Article 99. https://doi.org/10.3390/antiox8040099
[20]
Sudhakaran, M., Sardesai, S. and Doseff, A.I. (2019) Flavonoids: New Frontier for Immuno-Regulation and Breast Cancer Control. Antioxidants, 8, Article 103. https://doi.org/10.3390/antiox8040103
[21]
Lotito, S. and Frei, B. (2006) Consumption of Flavonoid-Rich Foods and Increased Plasma Antioxidant Capacity in Humans: Cause, Consequence, or Epiphenomenon? Free Radical Biology and Medicine, 41, 1727-1746. https://doi.org/10.1016/j.freeradbiomed.2006.04.033
[22]
Cutler, G.J., Nettleton, J.A., Ross, J.A., Harnack, L.J., Jacobs, D.R., Scrafford, C.G., et al. (2008) Dietary Flavonoid Intake and Risk of Cancer in Postmenopausal Women: The Iowa Women’s Health Study. International Journal of Cancer, 123, 664-671. https://doi.org/10.1002/ijc.23564
[23]
Alnakhli, J., Alhamed, S., Boadi, W. and Beni, R. (2023) Triphenylmethanol Conjugates of Triptorelin as Cell-Penetrating Anti-Cancer Prodrugs. Journal of Biosciences and Medicines, 11, 208-218. https://doi.org/10.4236/jbm.2023.1111018
[24]
Alhamed, S., Alnakhli, J., Boadi, W. and Beni, R. (2019) Triphenylmethanol Conjugates of Triptorelin as Anti-Lipid Peroxidation Prodrugs. Open Journal of Medicinal Chemistry, 9, 49-62. https://doi.org/10.4236/ojmc.2019.93003
[25]
Beni, R., Boadi, W., Karim, K., Alnakhli, J. and Alhamed, S. (2019) Synthesis and Antiproliferative Activities of Triphenylmethanol Conjugates of Leuprorelin. Open Journal of Medicinal Chemistry, 9, 37-47. https://doi.org/10.4236/ojmc.2019.92002
[26]
Shrestha, S., Bhattarai, B.R., Chang, K.J., Lee, K. and Cho, H. (2007) Methylenedisalicylic Acid Derivatives: New PTP1B Inhibitors That Confer Resistance to Diet-Induced Obesity. Bioorganic & Medicinal Chemistry Letters, 17, 2760-2764. https://doi.org/10.1016/j.bmcl.2007.02.069
[27]
Cushman, M., Kanamathareddy, S., De Clercq, E., Schols, D., Goldman, M.E. and Bowen, J.A. (1991) Synthesis and Anti-HIV Activities of Low Molecular Weight Aurintricarboxylic Acid Fragments and Related Compounds. Journal of Medicinal Chemistry, 34, 337-342. https://doi.org/10.1021/jm00105a053
[28]
Beni, R., Boadi, W., Alnakhli, J., Alhamed, S., Robinson, T., Mootry, M., et al. (2019) Triphenylmethanol and Tris(2-(Hydroxymethyl)Phenol) Derivatives: Synthesis and Application as Indicators for Acid-Base Volumetric Titration. Journal of Analytical Sciences, Methods and Instrumentation, 09, 13-21. https://doi.org/10.4236/jasmi.2019.92002
[29]
Alhawiti, N.M., Alramadhan, W.H., Boadi, W. and Myles, E.L. (2023) Anticancer Activity of Peganum harmala and Haloxylon salicornicum Leaf Extracts on Lung Cancer A549 and Prostate Cancer PC-3 Cell Lines. American Journal of Plant Sciences, 14, 1360-1374. https://doi.org/10.4236/ajps.2023.1411092
[30]
van Meerloo, J., Kaspers, G.J.L. and Cloos, J. (2011) Cell Sensitivity Assays: The MTT Assay. In: Cree, I., Ed., Methods in Molecular Biology, Humana Press, 237-245. https://doi.org/10.1007/978-1-61779-080-5_20
[31]
Ls, B. (2024) MPK phosphorylation Assay Kit (Fluorometric)#: LS-K268-100 by Life Span Biosciences Inc.
[32]
Aymoz, D., Wosika, V., Durandau, E. and Pelet, S. (2016) Real-Time Quantification of Protein Expression at the Single-Cell Level via Dynamic Protein Synthesis Translocation Reporters. Nature Communications, 7, Article No. 11304. https://doi.org/10.1038/ncomms11304
