Abstract 2139: Evaluation of a novel hypoxia-activated prodrug strategy in colorectal cancer cells

Abstract

Abstract Introduction: Current chemotherapeutic drugs are often ineffective against cancer cells that reside within the tumor microenvironment due to contributing factors such as hypoxia (low O2 tension) and acidic extracellular pH (pHe). Hypoxia is known to drive the aggressive cancer phenotype in many solid tumors, making it a key component of drug development. The use of hypoxia-activated prodrugs (HAPs) has been extensively studied over 40 years but to date no HAP has been approved for use in humans, largely because of poor activity and toxicity profiles. The design of prodrugs that are activated by both hypoxia and acidic pHe may provide a greater degree of selectivity and activity than HAPs alone, and this study was designed to evaluate a series of novel bromosugar-based HAPs under hypoxic and acidic pHe conditions. Method: A library of 13 HAPs was evaluated against HCT116 colorectal cancer cells and ARPE-19 human retinal epithelial noncancerous cell line. Cytotoxicity was determined under (i) aerobic condition (21% oxygen) at pHe 7.4 or mild acidic conditions (pHe 6.5) and (ii) hypoxic condition (0.1% oxygen) at pHe 7.4 or mild acidic conditions (pHe 6.5). ARPE-19 cells were only tested under aerobic conditions and pHe 7.4 to reflect normal physiologic conditions. Compounds were tested at different concentrations ranging from 0.1-100µM from which an IC50 value was determined. Cell survival was measured after a 96-hour continuous drug exposure using the MTT assay. Results: Among the compounds screened, DS10 demonstrated the most enhanced potency against HCT116 cells under hypoxic conditions with an IC50 value of 28.18 ± 7.01 µM as compared to an IC50 value of 66.39 ± 8.10 µM under normoxic conditions at pHe 7.4. Potency was further increased when DS10 was evaluated under a combination of hypoxic and acidic pHe conditions with an IC50 value of 16.30 µM ± 4.11. ARPE-19 cells showed an IC50 value of 42.95 µM ± 5.03 under aerobic conditions. Discussion: The results of this study demonstrated that bromosugar derivatives may have the potential to selectively target hypoxic cancer cells in an acidic extracellular environment. Specifically, DS10 exhibited potential HAP properties with the ability to target cells that reside within the hypoxic and acidic microenvironment of tumors. Selectivity to tumor cells as opposed to noncancer cells was observed under these conditions, suggesting that DS10 is a promising compound to take forward for further evaluation. Citation Format: Omar Hussain, Henrik Johansson, Simon J. Allison, Daniel S. Pedersen, Roger M. Phillips. Evaluation of a novel hypoxia-activated prodrug strategy in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2139.