The Biological Relevance of Papaverine in Cancer Cells

Abstract

Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the Papaverine somniferum plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits phosphodiesterase 10A (PDE10A,) resulting in the accumulation of cyclic adenosine 3', 5'-monophosphate (cAMP) that affects multiple downstream pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), a mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF). The accumulation of cAMP can further affect mitochondrial metabolism through the activation of protein kinase A (PKA), which activates the mitochondrial complex I. Literature has shown that PPV exerts anti-proliferative affects in several tumorigenic cell lines including adenocarcinoma alveolar cancer (A549) and human hepatoma (HepG-2) cell lines. Cell cycle investigations have shown varying results with the effects dependent on concentration and cell type with data suggesting an increase in cells occupying the sub-G₁ phase, which is indicative of cell death. These results suggest that PPV may be a beneficial compound to explore for the use in anticancer studies. More insight into the effects of the compound on cellular and molecular mechanisms is needed. Understanding the effects PPV may exert on tumorigenic cells may better researchers' understanding of phytomedicines and the effects of PPV and PPV-derived compounds in cancer.

Keywords: papaverine; phosphatidylinositol-3-kinase; phosphodiesterase 10A; vascular endothelial growth factor.

Figure 1

Chemical structure of PPV (Image designed by DA Gomes using ChemSpider (released in 2008, Royal Society of Chemistry, Raleigh, NC, USA).

Figure 2

Schematic diagram for the mechanisms underlying the anti-tumor effects of PDE10 inhibition in colon tumor cells. Intracellular cGMP levels are increased due to the inhibition of PDE10A preventing the breakdown to 5′GMP. This activates PKG, which results in the suppression of the expression of β-catenin and inhibits T-cell factor (TCF) transcription of target genes (e.g., survivin). The inhibition of PDE10A prevents breakdown of cAMP to 5′AMP, AC enzymes continue to form cAMP using ATP causing cAMP levels to increase [46]. cAMP activates PKA which phosphorylates CREB. CREB can then activate downstream signaling pathways that either stimulate or inhibit oncogene expression [42]. Image created DA Gomes using Microsoft^® office PowerPoint (Microsoft office enterprise 2007, 2006 Microsoft Corporation, Redmond, Washington, DC, USA).

Figure 3

Schematic diagram of the formation and function of the mitochondrial complex I. NDUFS4 is synthesized in the nucleus and transported to the cell cytosol. In the cytosol, PKA can phosphorylate it before it is transported into the mitochondria (not shown) or NDUFS4 is transported into the mitochondrial cytosol where it is phosphorylated by PKA. NDUFS4 then assists in the assembly of the mitochondrial complex I. The mitochondrial complex I can then oxidize NADH to 2NAD, transferring electrons via an electron chain to Ubiquinone (Q). Flavin mononucleotide (FMN) is the entry point for electrons from NADH; electrons are then transferred to iron–sulfur clusters with several different enzymes involved. The pathway of electron transport is indicated by the blue arrows. Ubiquinone is the final electron acceptor and is then reduced by coenzyme Q (coQ) to ubiquinol (QH₂) [55,56]. Image created by DA Gomes using Microsoft^® office PowerPoint (Microsoft office enterprise 2007, 2006 Microsoft Corporation, Redmond, Washington, DC, USA).

Figure 4

A schematic diagram of the mTOR and PI3K/Akt pathway. Raptor and rictor are two mTOR-interacting proteins that define 2 separate branches of the mTOR pathway. Raptor–mTOR pathway regulates cell growth through interactions with S6K1 and 4E-BP1 proteins. Nutrients can influence the response of the raptor–mTOR branch [61]. The rictor–mTOR pathway regulates Akt/PKB to control cell survival, proliferation, metabolism, and cytoskeleton formation. The binding of growth factors to receptors such as PDGF activates PI3K to generate Phosphatidylinositol (PtdIns) (3,4,5) P₃ from PtdIns (4,5) P₂. This recruits the PDK1 kinase and Akt/PKB to the membrane. PTEN is a tumor suppressor gene that regulates the activity of PI3K. Akt/PKB can then be activated by phosphorylation at 2 separate sites [61]. Rictor–mTOR complex phosphorylates Ser473 on Akt/PKB; this may lead to the phosphorylation of Akt/PKB on Thr308. The regulation of this complex is relatively unknown. Solid arrows indicate direct interactions and dash arrows indicate interactions that are indirect [61]. Image created by DA Gomes using Microsoft^® office PowerPoint (Microsoft office enterprise 2007, 2006 Microsoft Corporation, Redmond, Washington, DC, USA).