Marketed drugs used for the management of hypercholesterolemia as anticancer armament

Abstract

The design of novel pharmacologic agents as well as their approval for sale in markets all over the world is a tedious and pricey process. Inevitably, oncologic patients commonly experience unwanted effects of new anticancer drugs, while the acquisition of clinical experience for these drugs is largely based on doctor-patient partnership which is not always effective. The repositioning of marketed non-antineoplastic drugs that hopefully exhibit anticancer properties into the field of oncology is a challenging option that gains ground and attracts preclinical and clinical research in an effort to override all these hindrances and minimize the risk for reduced efficacy and/or personalized toxicity. This review aims to present the anticancer properties of drugs used for the management of hypercholesterolemia. A global view of the antitumorigenicity of all marketed antihypercholesterolemic drugs is of major importance, given that atherosclerosis, which is etiologically linked to hypercholesterolemia, is a leading worldwide cause of morbidity and mortality, while hypercholesterolemia and tumorigenesis are known to be interrelated. In vitro, in vivo and clinical literature data accumulated so far outline the mechanistic basis of the antitumor function of these agents and how they could find application at the clinical setting.

Keywords: antihypercholesterolemic agents; cancer; repurposing; synergism.

Figure 1

Signaling pathways mechanistically involved in atorvastatin’s ability to inhibit the migratory and invasive potential of different types of cancer cells in vitro. Notes: One of the mechanisms that have been reported in PTEN-positive prostate cancer cells involves the blockage of a purinergic P2X7/EHBP1/P-Rex1 route. On the other hand, the antimigratory/anti-invasive properties of atorvastatin in breast cancer cells have been linked to the downregulation of the expression of a series of different proteins, that is, uPA, the bHLH transcription factor Twist as well as MMP-9. In HNSCC cells, the ability of atorvastatin to inhibit cancer cell migration/invasion relays on the drug-induced impaired function of the small GTPase, RhoC. In NSCLC cells, atorvastatin hinders the metastatic potency through inhibiting TGF-β1–dependent pathways which are associated with the upregulation of SphK1 and the EMT-promoting transcription factor, ZEB1. Downward pointing arrows refer to negative regulation of the expression by atorvastatin. P-Rex1 exhibits GEF activity (ie, enables the release of GDP and the subsequent binding of a GTP molecule by a GTPase), whereas RhoC exhibits GTPase activity (ie, it catalyzes the hydrolysis of GTP to GDP). Abbreviations: ATP, adenosine triphosphate; bHLH, basic helix–loop–helix; EMT, epithelial-to-mesenchymal transition; GDP, guanosine diphosphate; GEF, guanine-nucleotide exchange factor; GTP, guanosine triphosphate; HNSCC, head and neck squamous cell carcinoma; MMP, matrix metalloproteinase; NSCLC, non-small cell lung cancer; PTEN, phosphate and tensin homolog deleted on chromosome 10; SphK1, sphingosine kinase 1; uPA, urokinase-type plasminogen activator.

Figure 2

Docking of simvastatin on the human DNA replication licensing factor CDT1. Notes: Autodock vina has been used to predict binding sites of simvastatin as a ligand (structure taken from Protein Data Bank, PDB:2WVR) on CDT1 (chain C, PDB:4XW2) allowing flexible docking for the ligand. Three of the nine predicted binding sites of similar affinity (~−5.5 kcal/mol) are positioned in the interaction interface between CDT1 and geminin (chains A and B, PDB:4XW2), indicating that simvastatin interferes with the CDT1:geminin complex and possibly destabilizes it. The figure has been produced using PyMol using the following coloring code: magenta for CDT1 in cartoon representation, green and cyan for the geminin dimer in surface representation, red, yellow and gray for the three poses of simvastatin in sticks representation.