Pharmacodynamic Drug-Drug Interaction Between Oxaliplatin and HDAC Inhibitors in Colorectal Cancer Cell Lines
Angelica Squarzoni (1), Mfonabasi Ette (2), Brent Boleslav (2), Elisabetta Donzelli (1), Arianna Scuteri (1), Guido Cavaletti (1), Donald E. Mager (2,3)
(1) School of Medicine and Surgery, University of Milano-Bicocca, Monza IT (2) Department of Pharmaceutical Sciences, University at Buffalo, SUNY (3) Enhanced Pharmacodynamics, LLC, Buffalo, NY, USA
Objectives:
Histone deacetylases (HDACs) are enzymes that regulate gene expression and that have been proposed as regulators for various signaling pathways [1]. The role of HDACs in neuroprotection and neurotoxicity has been studied to identify potential mechanisms and points of intervention [1,2]. The FDA has approved an increasing number of HDAC inhibitors (HDACi) [1], which have also been tested for other treatment indications and to protect against damage to the nervous system [2]. The classical chemotherapeutic treatment for colorectal cancer is oxaliplatin, a molecule that can cross-link to DNA to treat tumors but also generates several side effects [3]. One of the side effects is chemotherapy-induced peripheral neuropathy (CIPN), a pathology that can affect the sensory functions of the peripheral nervous system. These side effects can be short (weeks) or long (years) term and can affect patient quality of life [4]. There is no effective treatment available for CIPN. Our long-term goal is to identify combination therapy with the potential to limit CIPN side effects. The purpose of this study is to identify the effect of the combination of HDACi and oxaliplatin on a panel of colorectal cancer cell lines. This is a first step to evaluate the efficacy of the combination in cancer cells and whether there are any potential advantages of specific HDACi based on signal transduction.
Methods: Cytotoxicity data were obtained using an SRB assay, a colorimetric assay used to verify cell survival, on a 96-well plate. Drugs were tested as single and combination treatments in three colorectal cancer cell lines (HT-29, HCT-15, and CaCo-2) [5]. Six different HDACi were considered (Vorinostat, Belinostat, Romidepsin, Ricolinostat, Panobinostat, and SW-100) in combination with oxaliplatin (OHP). Pharmacodynamic modeling and simulations were conducted through the Simulx program (Lixoft, Monolix suite) to determine individual drug potencies (inhibitory Emax model), and interactions were simulated assuming additivity with both competitive and non-competitive equations to compare with experimental data [6,7].
Results: The potencies of individual drugs were determined in all 3 cell lines, and the IC50 values ranged from 2.2 to 5 µM for OHP, 1 to 6 µM for Vorinostat, 0.4 to 1.6 µM for Belinostat, 2.5 to 370 nM for Romidepsin, 7.5 to 15 µM for SW-100, 16 to 161 nM for Panobinostat, and from 5 to 30 µM for Ricolinostat. All combination pharmacodynamic experiments were simulated assuming additivity with both competitive and non-competitive equations [7], resulting in two sets of predictions for the three colorectal cancer cell lines. For the competitive simulation, just one third of the treatments were consistent with an additive interaction, whereas the other treatments were slightly less than additive. Vorinostat was consistently less then additive in all cell lines while Romidepsin was consistently additive. The treatment with Belinostat and Ricolinostat were consistently additive in CaCo-2 and HT-29 cell lines. For the non-competitive simulation, just two results (Romidepsin for HT-29 and for HCT-15) agreed with additivity whereas all others were slightly less than additive.
Conclusions: The pharmacodynamic interaction between oxaliplatin and six HDACi appears to be additive or slightly less than additive in the three colorectal cancer cell lines based on final simulations. This analysis will serve as a basis for investigating the molecular mechanisms underlying the combination drug effects.
References:
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