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

Hou, Yali; Wren, Alexis; Mylarapu, Namratha; Browning, Kaylin; Islam, Bianca N.; Wang, Rui; Vega, Kenneth J.; Browning, Darren D.

doi:10.1124/jpet.121.001075

Cited by 8 publications

(3 citation statements)

References 46 publications

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“…13,14,25,33 While a recent study has found that PDE10A inhibition blocked colon cancer cell growth independent of cGMP signaling. 34 During the preparation of this article, a new published study reported that PDE10A inhibition decreases ovarian cancer growth and induces apoptosis, which supports our observation in ovarian cancer cells and in nude mice xenograft. 35 In addition, a PDE10A single-nucleotide polymorphism variant in a noncoding exon is associated with the risk of tobacco-induced developing non-small-cell lung cancer.…”

Section: Discussionsupporting

confidence: 83%

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Chen

et al. 2023

Circulation Research

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BACKGROUND: Cyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX. METHODS: We used global PDE10A KO (knockout) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies. RESULTS: We found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA- (protein kinase A) and cGMP/PKG-dependent signaling. CONCLUSIONS: Taken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

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Section: Discussionsupporting

confidence: 83%

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Chen

et al. 2023

Circulation Research

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“…This suggests that the expression of Pde11a can regulate the development of glioblastoma in patients. other Pdes (Pde5, Pde8, and Pde10) are also involved in cancer cell proliferation; various mutations have been described (96)(97)(98). Therefore, Pde11a and other Pdes fail to act as regulators of caMP and cGMP, affecting the growth and development of cancer cells.…”

Section: Pde11a and Tumorsmentioning

confidence: 99%

Functional characteristics and research trends of PDE11A in human diseases (Review)

Kong

Lee

et al. 2022

Mol Med Rep

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caMP and cGMP are important secondary messengers involved in cell regulation and metabolism driven by the G protein-coupled receptor. caMP is converted via adenylyl cyclase (ac) and activates protein kinase a to phosphorylate intracellular proteins that mediate specific responses. cAMP signaling serves a role at multiple steps in tumorigenesis. The level of caMP is increased in association with cancer cell formation through activation of ac-stimulatory G protein by mutation. Phosphodiesterases (Pdes) hydrolyze caMP and cGMP to aMP and GMP. Pdes are composed of 11 families, and each can hydrolyze caMP and cGMP or both caMP and cGMP. Pdes perform various roles depending on their location and expression site, and are involved in several diseases, including male erectile dysfunction, pulmonary hypertension, alzheimer's disease and schizophrenia. Pde11a is the 11th member of the Pde family and is characterized by four splice variants with varying tissue expression and n-terminal regulatory regions. among tissues, the expression of Pde11a was highest in the prostate, and it was also expressed in hepatic skeletal muscle, pituitary, pancreas and kidney. Pde11a is the first PDE associated with an adrenocortical tumor associated genetic condition. in several studies, three Pde11a mutations have been reported in patients with cushing syndrome with primary pigmented nodular adrenocortical disease or isolated micronodular adrenocortical disease without other genetic defects. it has been reported that an increase in Pde11a expression affects the proliferation of glioblastoma and worsens patient prognosis. The present mini-review summarizes the location of Pde11a expression, the impact of structural differences and disease relevance. Contents1. introduction 2. caMP/cGMP-dependent signaling 3. Phosphodiesterase family 4. Pde11a and tumors 5. other diseases cause by Pde11a 6. Further focus for Pde11a

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“…Cells were treated with 1 μM linaclotide together with different PDE5i concentrations for 4h, followed by processing of cell extracts for cellular cGMP measurement using cGMP ELISA kits according to the manufacturer instructions (Cayman Chemical). To assess activation of cGMP signaling by immunoblotting, we used LS174T cells with inducible PKG2 expression that were described recently (Hou et al, 2022).…”

Section: In Vitro Pharmacology and Permeability Assaysmentioning

confidence: 99%

A non-systemic phosphodiesterase-5 inhibitor suppresses colon proliferation in mice

Lee

Lebedyeva

Zhi

et al. 2022

Preprint

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Background and Purpose: Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing as an intervention for colon cancer prevention. A drawback to conventional PDE5i are side-effects and drug-drug interactions that would be poorly tolerated when taken on a chronic basis for prevention. Experimental Approach: We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity and measured its entry into the circulation and effects on colon epithelium. Key Results: This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil (6.5 nM vs 7.5 nM respectively) but exhibited almost 100-fold reduced cell entry compared to sildenafil. Using an LC-MS/MS approach, doses of malonyl-sildenafil up to 36 mg/kg were barely detectable in mouse plasma after oral administration but was detected at high levels in the feces. This contrasted with sildenafil that was detected in the plasma but not in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. Treatment of mice with malonyl-sildenafil in the drinking water for 8 days was well-tolerated and resulted in a suppression of proliferation in the colon epithelium that is consistent with results published previously for mice treated with PDE5i. Conclusion and Implications: A carboxylic acid-containing analog of sildenafil prohibits systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generate a first in class drug for colon cancer chemoprevention.

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

Cited by 8 publications

References 46 publications

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth

Functional characteristics and research trends of PDE11A in human diseases (Review)

A non-systemic phosphodiesterase-5 inhibitor suppresses colon proliferation in mice

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