A novel phosphodiesterase target as a therapeutic approach: inhibiting DEN-induced hepatocellular carcinoma progression

Abstract

Hepatocellular Carcinoma (HCC) is one of the most common and fatal types of liver cancer worldwide; in this sense, Diethylnitrosamine (DEN) has been established as a potent carcinogen affecting the development and progression of this disease. The present work focused on determining whether phosphodiesterase (PDE) enzymes, especially PDE5, may serve as targets in the therapeutic treatment of DEN-induced HCC. PDE5 inhibitors, widely used as therapeutic drugs for cardiovascular diseases and erectile dysfunction, have recently been found to be promising in preclinical cancer models through the modulation of key signaling pathways implicated in the progression of tumors, such as the cGMP-PKG, JNK, and MAPK pathways. These pathways are very important for cell proliferation, apoptosis and metastasis, and their dysregulation contributes to the aggressive nature of HCC. This study assessed the potential of PDE5 inhibitors to suppress proliferation, induce apoptosis, and alter the tumor microenvironment, thus potentially improving standard chemotherapy and immunotherapy interventions. By inhibiting certain PDE isoforms with these drugs, an anticancer response might occur as part of a complex mechanism that acts on both cancer cells and the microenvironment favorable for tumor growth. A preliminary review indicated that PDE inhibitors may be a promising therapeutic approach for overcoming some of the shortcomings of current treatments, particularly the development of resistance and the toxic effects of these treatments. Additional clinical investigations are necessary to determine the safety profile, appropriate amount of Osage, and long-term efficacy of these agents in the treatment of HCC, particularly in DEN-induced animal models. This study contributes to the expanding body of evidence supporting the use of PDE inhibitors in cancer treatment.

Keywords: Diethylnitrosamine (DEN); HCC; JNK pathway; MAPK pathway; PDE5; Phosphodiesterase (PDE) inhibitors; cGMP-PKG pathway; cancer therapy; tumor microenvironment.

Table 1. Role of phosphodiesterase inhibitors in cancer biology

Table 2. A comparative analysis of in vivo and in vitro findings related to the use of PDE inhibitors in cancer models

Table 3. Key studies on PDE inhibitors in various cancers

Table 4. Short overview of PDE inhibitors in comparison to other HCC treatments currently on the market

Table 5. PDE5 inhibitors as an adjunct to current HCC therapies

Figure 1. Multiple types of carcinomas in humans and rats

Figure 2. Stages of normal liver to hepatocellular carcinoma

Figure 3. Fifty-two signaling pathways that include the cAMP-cGMP transduction cascade were identified.