PAK1-blockers: Potential Therapeutics against COVID-19

Hiroshi Maruta, Hong He, Hiroshi Maruta, Hong He

Abstract

PAK1 (RAC/CDC42-activated kinase 1) is the major "pathogenic" kinase whose abnormal activation causes a wide variety of diseases/disorders including cancers, inflammation, malaria and pandemic viral infection including influenza, HIV and COVID-19. Since Louis Pasteur who developed a vaccine against rabies in 1885, in general a series of "specific" vaccines have been used for treatment of viral infection, mainly because the majority of pre-existing antibiotics are either anti-bacterial or anti-fungal, thereby being ineffective against viruses in general. However, it takes 12-18 months till the effective vaccine becomes available. Until then ventilator (O2 supplier) would be the most common tool for saving the life of COVID-19 patients. Thus, as alternative potentially more direct "broad-spectrum" signalling mechanism-based COVID-19 therapeutics, several natural and synthetic PAK1-blockers such as propolis, melatonin, ciclesonide, hydroxy chloroquine (HQ), ivermection, and ketorolac, which are readily available in the market, are introduced here.

Keywords: COVID-19; PAK1; cancer; pathogenic kinase; viral infection.

© 2020 Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
PTEN, a PAK1-blocker, interferes with coronavirus –induced PAK1-dependent signalling pathway leading to lung fibrosis.
Fig. 2
Fig. 2
"Double" blows of PAK1-blockers against viral infection
Fig. 3
Fig. 3
Effective daily dose for COVID-19: 600mg.

References

    1. Gordon CJ, Tchesnokov EP, Feng JY, et al (2020). The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem. pii: jbc.AC120.013056.
    1. Maruta H. Tackling the Coronaviral Infection: Blocking Either the “Pathogenic” Kinase PAK1 or RNA-dependent RNA Polymerase (RdRP) J Infect Dis Ther. 2020;8(2):418.
    1. Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res. 2014;28:656–672.
    1. Xu J.W., Ikeda K., Kobayakawa A., Ikami T. Downregulation of Rac1 activation by caffeic acid in aortic smooth muscle cells. Life Sci. 2005;76:2861–2872.
    1. Vincent M.J., Bergeron E., Benjannet S. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2:69.
    1. Oh S., Shin J.H., Jang E.J. Anti-inflammatory activity of chloroquine and amodiaquine through p21-mediated suppression of T cell proliferation and Th1 cell differentiation. Biochem Biophys Res Commun. 2016;474:345–350.
    1. Lu S., Strand K.A., Mutryn M.F. PTEN (Phosphatase and Tensin Homolog) Protects Against Ang II (Angiotensin II)-Induced Pathological Vascular Fibrosis and Remodeling-Brief Report. Arterioscler Thromb Vasc Biol. 2020;40:394–403.
    1. Chen I.Y., Chang S.C., Wu H.Y. Upregulation of the chemokine (C-C motif) ligand 2 (CCL2) via a severe acute respiratory syndrome coronavirus spike-ACE2 signaling pathway. J Virol. 2010;84:7703–7712.
    1. Huynh N., Wang K., Yim M. Depletion of p21-activated kinase 1 (PAK1) up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis. BMC Cancer. 2017;17:431.
    1. Grunberger D., Banerjee R., Eisinger K. Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia. 1988;44:230–232.
    1. Nguyen B.C., Yoshimura K., Kumazawa S., Tawata S., Maruta H. Frondoside A from Sea Cucumber and Nymphaeols from Okinawa Propolis: Natural anti-cancer agents that selectively inhibit PAK1 in vitro, Drug Discov. Ther. 2017;11:110–114.
    1. Maruta H., Ahn M.R. From bench (laboratory) to bed (hospital/home): How to explore effective natural and synthetic PAK1-blockers/Longevity-promoters for cancer therapy. Eur. J. Med. Chem. 2017;142:229–243.
    1. Reiter R., Robinson J. Bantan Books; New York: 1995. Melatonin: Your Body's Natural Wonder Drug.
    1. Be Tu P.T., Nguyen B.C., Tawata S. The serum/PDGF-dependent “melanogenic” role of the minute level of the oncogenic kinase PAK1 in melanoma cells proven by the highly sensitive kinase assay. Drug Discov Ther. 2017;10:314–322.
    1. Allen JD, Jaffer ZM, Park SJ, et al. (2009). p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics. Blood. 19;113(12):2695–705.
    1. Choi HS, Kim SL, Kim JH, Lee DS (2020). The FDA-Approved Anti-Asthma Medicine Ciclesonide Inhibits Lung Cancer Stem Cells through Hedgehog Signaling-Mediated SOX2 Regulation. Int J Mol Sci, 21(3). pii: E1014.
    1. Liou J.T., Chen Z.Y., Ho L.J. Differential effects of triptolide and tetrandrine on activation of COX-2, NF-kappaB, and AP-1 and virus production in dengue virus-infected human lung cells. Eur J Pharmacol. 2008;589:288–298.
    1. Patil S., Lis L.G., Schumacher R.J. Phosphonooxymethyl Prodrug of Triptolide (Minnelide): Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts. J. Med. Chem. 2015;58:9334–9344.
    1. Hashimoto H., Messerli S.M., Sudo T., Maruta H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009;3:243–246.
    1. Chen H., Sun B., Pan S., Jiang H. Dihydroartemisinin inhibits growth of pancreatic cancer cells in vitro and in vivo. Anticancer Drugs. 2009;20:131–140.
    1. Sicard A., Semblat J.P., Doerig C., Hamelin R. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Cell Microbiol. 2011;13:836–845.
    1. Wang J.X., Tang W., Shi L.P., Wan J. Investigation of the immune-suppressive activity of artemether on T-cell activation and proliferation. Brit. J. Pharmacol. 2007;150:652–661.
    1. Hirokawa Y., Nheu T., Grimm K. Sichuan pepper extracts block the PAK1/cyclin D1 pathway and the growth of NF1-deficient cancer xenograft in mice. Cancer Biol Ther. 2006;5:305–309.
    1. Nakajima H., Kim Y.B., Terano H., Yoshida M., Horinouchi S. FK228, a potent anti-tumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res. 1998;241:126–133.
    1. Hirokawa Y., Arnold M., Nakajima H., Zalcberg J., Maruta H. Signal therapy of breast cancer xenograft in mice by the HDAC inhibitor FK228 that blocks the activation of PAK1 and abrogates the tamoxifen-resistance. Cancer Biol. Ther. 2005;4:956–960.
    1. Gautret P., Lagier J.C., Parola P. Hydroxychloroquine (HQ) and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar;20:105949.
    1. Li F., Huang J., Ji D. Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer. Oncol Lett. 2017;14:89–96.
    1. Guo Y., Kenney S.R., Jr., Muller C.Y. R-ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis. Mol. Cancer Ther. 2015;14:2215–2227.
    1. Nguyen B.C., Takahashi H., Uto Y., Shahinozzaman M.D., Tawata S., Maruta H. 1,2,3-Triazolyl ester of Ketorolac: A “Click Chemistry”-based highly potent PAK1-blocking cancer-killer. Eur J Med Chem. 2016;126:270–276.
    1. Hennig R., Albawardi A., Almarzooqi S. 1,2,3-Triazolyl Ester of Ketorolac (15 K), a Potent PAK1-Blocker. Inhibits Both Growth and Metastasis of Human Pancreatic Cancer Orthotopic Xenografts in Mice. Drug Discov.Ther. 2019;13:248–255.
    1. Eisman J.A., Barkla D.H., Tutton P.J. Suppression of in vivo growth of human cancer solid tumor xenografts by 1,25-dihydroxyvitamin D3. Cancer Res. 1987;47:21–25.
    1. Flanagan J.N., Zheng S., Chiang K.C. Evaluation of 19-nor-2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D3 (MART-10) as a therapeutic agent for androgen-dependent prostate cancer. Anticancer Res. 2009;29:3547–3553.
    1. Zeng N., Salker M.S., Zhang S. 1α,25 (OH) 2D3 Induces Actin Depolymerization in Endometrial Carcinoma Cells by Targeting RAC1 and PAK1. Cell Physiol Biochem. 2016;40:1455–1464.
    1. Chiang KC, Yeh TS, Chen SC, et al. (2016). The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential. Int J Mol Sci. 17, pii: E606.
    1. Dwivedi P.P., Omdahl J.L., Kola I., Hume D.A., May B.K. Regulation of rat cytochrome P450C24 (CYP24) gene expression. Evidence for functional cooperation of Ras-activated Ets transcription factors with the vitamin D receptor in 1,25-dihydroxyvitamin D(3)-mediated induction. J Biol Chem. 2000;275:47–55.

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