Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes

Abstract

Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA cross-linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA cross-linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40–80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ∼5 μM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications.

Evaluation of HO-1 expression, cellular ROS production, cellular proliferation and cellular apoptosis in human esophageal squamous cell carcinoma tumors and cell lines

“…Evidence has shown that the expression of HO-1 was increased by HIF-1α (12,13). Moreover, oxidation stress exists in tumors (14). Additionally, we found that HO-1 is positively correlated with HIF-1α.…”

“…Various ROS are always found in normally functioning cells and are thought to be a normal part of cell growth, proliferation and differentiation. ROS are usually found in very high levels in tumor cells (14). These high intracellular levels could affect normal cellular function and may contribute to tumor progression (17,18) We hypothesized that the decrease in HO-1 expression and ROS levels may affect the expression of apoptosis-related proteins.…”

Photoinduced DNA Interstrand Cross‐Link Formation by Naphthalene Boronates via a Carbocation

“…[13] Very recently, our group discovered that photoirradiation of several phenyl boronates efficiently produced bifunctional benzyl cations cross-linking DNA at dG and dC sites.…”

Hydrogen Sulfide Triggered Charge-Reversal Micelles for Cancer-Targeted Drug Delivery and Imaging

“…18 However, to date, most of the reported charge reversal of nano-drug carriers depend on the change of pH profile of cancer cells . [16][17][18] It is well know that cancer cells also produce high amounts of superoxide, [19][20][21] hydrogen peroxide, 22-24 hydroxyl radicals 25 and hydrogen sulfide. 26 .…”