Pros and Cons of Pharmacological Manipulation of cGMP-PDEs in the Prevention and Treatment of Breast Cancer.

Patrizia Di Iorio,Mariachiara Zuccarini,Francesco Caciagli,Patricia Giuliani,Renata Ciccarelli,Vanni Caruso,Maurizio Ronci,Sarah Beggiato

doi:10.3390/ijms23010262

Patrizia Di Iorio, Mariachiara Zuccarini + Show 6 more

Open Access

https://doi.org/10.3390/ijms23010262

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Abstract

The cyclic nucleotides, cAMP and cGMP, are ubiquitous second messengers responsible for translating extracellular signals to intracellular biological responses in both normal and tumor cells. When these signals are aberrant or missing, cells may undergo neoplastic transformation or become resistant to chemotherapy. cGMP-hydrolyzing phosphodiesterases (PDEs) are attracting tremendous interest as drug targets for many diseases, including cancer, where they regulate cell growth, apoptosis and sensitization to radio- and chemotherapy. In breast cancer, PDE5 inhibition is associated with increased intracellular cGMP levels, which is responsible for the phosphorylation of PKG and other downstream molecules involved in cell proliferation or apoptosis. In this review, we provide an overview of the most relevant studies regarding the controversial role of PDE inhibitors as off-label adjuvants in cancer therapy.

Highlights

In accordance with the latest epidemiological data, breast cancer is the most frequently diagnosed cancer in women [1]
The same research group, in a later work, specified that the Cyclic guanosine monophosphate (cGMP)-mediated inhibition of breast tumor cell growth by sulindac sulfide or known PDE5 pharmacologic inhibitors (e.g., MY5445 and tadalafil) was due to the degradation of nuclear β-catenin following its phosphorylation at the serine 33–37, or threonine 41 residues by PKG and, as a consequence, the suppression of oncogenes regulated by β-catenin, including survivin and vasodilator-stimulated phosphoprotein (VASP)
Carcinogenesis is the result of the accumulation of genetic mutations, which allow cells to escape from diverse mechanisms of growth control and programmed death

Summary

Introduction

In accordance with the latest epidemiological data, breast cancer is the most frequently diagnosed cancer in women [1]. Mujoo et al demonstrated that sGC activators, given alone or in combination with NO donors, were able to suppress tumor growth in ovarian, breast, and prostate cancer cell lines [43] In these cells the common downstream effector, cGMP, reduced tumor cell proliferation. In another study on human ovarian cancer cells, the cGMP analog 8-Br-cGMP was shown to promote cell viability through the inhibition of caspase3-mediated apoptosis and the degradation of p53, this effect being reverted by cell pre-treatment with the sGC inhibitor ODQ [44] This tumorigenic activity was reported in metastatic C3L5 mammary cell line expressing high levels of eNOS, where a NO/sGC/cGMP/ERK signaling cascade was responsible for increased cell motility by virtue of vascular endothelial growth factor (VEGF) and. This finding is in accordance with other studies highlighting the importance of mitochondrial compartmentalization of several enzymes and their substrates in hypoxic tumor environment [46,47]

Challenges of Targeting cGMP Signaling in Breast Cancer

Findings

Concluding Remarks