Selected Statins as Dual Antiproliferative-Antiinflammatory Compounds

Abstract

Background: We hypothesized that superlative dual cytotoxicity-antiinflammtion bioefficacies of 9 selected lipophilic statins correlate to their chelation effect of 3,5-dihydroxyheptanoic acid.

Methodology: Lipophilic-acid chelating statins have been screened for in vitro duality of proliferation inhibition and NO-radical scavenging capacities.

Results: Their spectrum of selectivity indices for safety in PDL fibroblasts -based 72h incubations was reported. Surprisingly despite its lack on macrophages LPS-triggered inflammation over 5-200 µM and unlike the 8 statins; cerivastatin had growth inhibition IC50 values of 40nM (SW620), 110nM (HT29), 2.9 µM (HCT116), 6µM (SW480), and most notably 38µM (<50 µM, in Caco2). Exclusively cerivastatin exerted antitumorigenesis IC50 values <50 µM in all T47D, MCF7 and PANC1 72h cultures. In statins with greater antiinflammation affinity than indomethacin's; lovastatin had cytotoxicity IC50 values <20 µM in SW620<HT29<ACT116100 µM in Caco2. Atorvastatin was found of viability reduction IC50 value <20 µM in HCT11650µM in T47D, MCF7 and PANC1. Rosuvastatin had antineoplastic IC50 values (<50 µM) in SW620<SW48050 µM in remaining colorectal, breast and pancreatic cancer cell lines. In statins with appreciable antiinflammation but reasonably lower affinity than indomethacin's and cytotoxicity IC50 values >50µM in T47D, MCF7 and PANC1; pravastatin had viability reduction IC50 values <50µM in HT2950 µM were for statins in remaining colorectal cancer cell lines, breast cancer and pancreatic cancer cell lines.

Conclusion: Among the rest, cerivastatin warrants further novel scaffold development to maximize efficacy and optimal molecular action mechanisms of chemotherapy/prevention.

Keywords: Inflammation; Statins; Sulforhodamine B- Cisplatin; cancer and Chelation.

Figure 1

Proposed Structural Functionalities Required for Antiproliferative Effect in Atorvastatin

Figure 2

Structure of Pitavastatin Ca, Pravastatin and Rosuvastatin

Figure 3

Potential Enzymatic Hydrolysis of the Lactone into Active Free Acid

Figure 4

SARS of Antiproliferative Lipophilic Statins: acidic, lipohilic and H-B chelators are the essential features

Figure 5

A, Type 1 statins. B, Type 2 Statins

Figure 6

Dihydroxyheptanoic Acid Stero- Effect on Target Binding

Figure 7A

Tridentate-Chelation Groups Functionalities Shared by All Antiproliferating CRC: Statins, FQs, Doxorubicin

Figure 7B

Most Potent Antiproliferative Activity of Doxorubicin vs. atorvastatin on 5 CRC cell lines (IC₅₀ values below 50 μM for both treatments on HCT116 and SW620)

Figure 7C

Cerivastatin Cytotoxicity against Cell Lines (T47D, MCF7 and PANC-1) in Comparison with FQ (4b; 3-chloro aniline FQ), IC₅₀ values below 50μM

Figure 8

Statins 3, 5-dihydroxyheptanoic Acid as Chelator Group in Cerivastatin