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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Inhibition of Colon Cancer Cell Growth by Phosphodiesterase Inhibitors Is Independent of cGMP Signaling

Yali Hou, Alexis Wren, Namratha Mylarapu, Kaylin Browning, Bianca N. Islam, Rui Wang, Kenneth J. Vega and Darren D. Browning
Journal of Pharmacology and Experimental Therapeutics April 2022, 381 (1) 42-53; DOI: https://doi.org/10.1124/jpet.121.001075
Yali Hou
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Alexis Wren
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Namratha Mylarapu
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Kaylin Browning
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Bianca N. Islam
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Rui Wang
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Kenneth J. Vega
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Darren D. Browning
Department of Biochemistry and Molecular Biology (Y.H., A.W., N.M., K.B., D.D.B.) and Department of Medicine, Section of Gastroenterology and Hepatology (K.J.V.), Augusta University, Augusta, Georgia; and Department of Internal Medicine (B.N.I.) and Department of Surgery (R.W.), Case Western Reserve University, Cleveland, Ohio
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Abstract

There is growing interest in the potential use of phosphodiesterase (PDE) inhibitors for colorectal cancer (CRC) prevention and treatment. The present study has tested the idea that PDE inhibitors inhibit growth and viability of CRC cell lines by increasing cyclic guanosine monophosphate (cGMP) and activating cGMP-dependent protein kinase (PKG). Colon cancer cell lines and those with ectopic PKG2 expression were treated with membrane-permeable 8Br-cGMP or inhibitors of PDE5, PDE9, and PDE10a. Levels of cGMP capable of activating PKG were measured by immunoblotting for phosphorylation of vasodilator-stimulated phosphoprotein (VASP). The effects of treatment on CRC cell proliferation and death were measured using hemocytometry with trypan blue. Treatment with 8Br-cGMP had no effect on CRC cell proliferation or death. Endogenous PKG activity was undetectable in any of the CRC cells, but expression of ectopic PKG2 conferred modest inhibition of proliferation but did not affect cell death. Extremely high concentrations of all the PDE inhibitors reduced proliferation in CRC cell lines, but none of them increased cGMP levels, and the effect was independent of PKG expression. The inability of the PDE inhibitors to increase cGMP was due to the lack of endogenous cGMP generating machinery. In conclusion, PDE inhibitors that target cGMP only reduce CRC growth at clinically unachievable concentrations, and do so independent of cGMP signaling through PKG.

SIGNIFICANCE STATEMENT A large number of in vitro studies have reported that PDE inhibitors block growth of colon cancer cells by activating cGMP signaling, and that these drugs might be useful for cancer treatment. Our results show that these drugs do not activate cGMP signaling in colon cancer cells due to a lack of endogenous guanylyl cyclase activity, and that growth inhibition is due to toxic effects of clinically unobtainable drug concentrations.

Footnotes

    • Received December 22, 2021.
    • Accepted December 29, 2021.
  • This work was supported by a grant from the National Institutes of Health [Grant CA172627‐01A1] (to D.D.B.), and by a grant from the Georgia Research Alliance [GRA.VL21.E1] (to D.D.B.).

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/jpet.121.001075.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 1
1 Apr 2022
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Off-Target Effect of PDE Inhibitors on Colon Cancer

Yali Hou, Alexis Wren, Namratha Mylarapu, Kaylin Browning, Bianca N. Islam, Rui Wang, Kenneth J. Vega and Darren D. Browning
Journal of Pharmacology and Experimental Therapeutics April 1, 2022, 381 (1) 42-53; DOI: https://doi.org/10.1124/jpet.121.001075

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Off-Target Effect of PDE Inhibitors on Colon Cancer

Yali Hou, Alexis Wren, Namratha Mylarapu, Kaylin Browning, Bianca N. Islam, Rui Wang, Kenneth J. Vega and Darren D. Browning
Journal of Pharmacology and Experimental Therapeutics April 1, 2022, 381 (1) 42-53; DOI: https://doi.org/10.1124/jpet.121.001075
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