Could drugs inhibiting the mevalonate pathway also target cancer stem cells?

Abstract

Understanding the connection between metabolic pathways and cancer is very important for the development of new therapeutic approaches based on regulatory enzymes in pathways associated with tumorigenesis. The mevalonate cascade and its rate-liming enzyme HMG CoA-reductase has recently drawn the attention of cancer researchers because strong evidences arising mostly from epidemiologic studies, show that it could promote transformation. Hence, these studies pinpoint HMG CoA-reductase as a candidate proto-oncogene. Several recent epidemiological studies, in different populations, have proven that statins are beneficial for the treatment-outcome of various cancers, and may improve common cancer therapy strategies involving alkylating agents, and antimetabolites. Cancer stem cells/cancer initiating cells (CSC) are key to cancer progression and metastasis. Therefore, in the current review we address the different effects of statins on cancer stem cells. The mevalonate cascade is among the most pleiotropic, and highly interconnected signaling pathways. Through G-protein-coupled receptors (GRCP), it integrates extra-, and intracellular signals. The mevalonate pathway is implicated in cell stemness, cell proliferation, and organ size regulation through the Hippo pathway (e.g. Yap/Taz signaling axis). This pathway is a prime preventive target through the administration of statins for the prophylaxis of obesity-related cardiovascular diseases. Its prominent role in regulation of cell growth and stemness also invokes its role in cancer development and progression. The mevalonate pathway affects cancer metastasis in several ways by: (i) affecting epithelial-to-mesenchymal transition (EMT), (ii) affecting remodeling of Abbreviations: ACAT, acetoacetyl-CoA transferase; acetyl-CoA, acetyl-coenzyme A; Arp2/3, actin-related protein 2/3 (actin polymerizing complex) BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4. 0/). 14 W. Likus et al. / Drug Resistance Updates 25 (2016) 13-25 the cytoskeleton as well as cell motility, (iii) affecting cell polarity (non-canonical Wnt/planar pathway), and (iv) modulation of mesenchymal-to-epithelial transition (MET). Herein we provide an overview of the mevalonate signaling network. We then briefly highlight diverse functions of various elements of this mevalonate pathway. We further discuss in detail the role of elements of the mevalonate cascade in stemness, carcinogenesis, cancer progression, metastasis and maintenance of cancer stem cells.

Human Gyrovirus-Apoptin Interferes with the Cell Cycle and Induces G2/M Arrest Prior to Apoptosis

“…Many viruses preferentially or exclusively replicate in dividing cells; hence, their components are potentially becoming an important source/inspiration in the search of drugs that preferentially target cancer stem cells (AkbariBirgani et al 2016;Farahani et al 2014;Wasik et al 2014). Beside viral methods, some clinically tested as well as new drugs with preferential toxicity towards cancer stem cells are increasingly becoming available (Jangamreddy et al 2013;Likus et al 2016b;Moosavi et al 2016). Such tasks are facilitated by recent progress in methodologies that allows for better detection and monitoring of cancer stem While it is unlikely that a universal cancer cure will be found, rapid development will certainly lead to efficient anticancer strategies targeting groups of cancers.…”

Structure and properties of slow-resorbing nanofibers obtained by (co-axial) electrospinning as tissue scaffolds in regenerative medicine

“…Beside viral methods, some clinically tested as well as new drugs with preferential toxicity towards cancer stem cells are increasingly becoming available [37][38][39][40][41]. Such tasks are facilitated by recent progress in methodologies that allows for better detection and monitoring of cancer stem cells [25,26,39]. Assessment of the electrospinned nanofibres.…”

The role of statins as therapeutic agents in cancer

“…Among statins, cerivastatin, simvastatin, and lovastatin are most lipophilic, followed by mevastatin, fluvastatin, atorvastatin, rosuvastatin, and pravastatin (Likus et al 2016). Pravastatin is extremely hydrophilic compared to the other statins.…”

“…The product of HMG-CoA reductase activity, mevalonic acid, is a precursor of cholesterol and the isoprenoid intermediates farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Both FPP and GGPP play a central role in the process of prenylation, where FPP or GGPP are post-translationally added to a protein to facilitate cell membrane anchoring (Ghavami et al 2012(Ghavami et al , 2014Likus et al 2016). Isoprenoids are necessary for the post-translational modification of different proteins, such as GTPase proteins (Rho, Rac and Ras), which are important in many physiological processes.…”

“…They are beneficial for the treatment outcome of various types of cancer, while they may improve common cancer therapy strategies involving alkylating agents and antimetabolites (Han et al 2011;Gopalan et al 2013;Kim et al 2014;Stoehr et al 2014;Blahovcova et al 2016;Likus et al 2016;Liang et al 2017).…”