A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells

Abstract

Ht-2 is a novel oxaliplatin derivative previously identified in a compound screen performed by our laboratory. In the present study, we evaluated the antitumor effects of Ht-2 and investigated its underlying mechanism of action. Ht-2 exhibited anti-tumor activity and demonstrated low cytotoxicity in normal cells in vitro. The IC50 of Ht-2 was 2-10-fold lower than oxaliplatin in all of the cancer cell lines tested except MCF-7 cells, whereas, the value was threefold higher than cisplatin or oxaliplatin in normal HUVEC cells. Further studies indicated that Ht-2 caused S-phase arrest and led to apoptosis in HCT-116 cells through the activation of the caspase cascade. Moreover, Ht-2 treatment contributed to increased mitochondrial permeability by altering the Bax/Bcl-2 ratio and consequently induced mitochondrial dysfunction, mitochondrial membrane potential depletion, reactive oxygen species (ROS) elevation and cytochrome C release in HCT-116 cells. The cellular antioxidative superoxide dismutase 1 protein was also downregulated. We demonstrated that the cytotoxicity was almost completely recovered by antioxidant treatment, indicating a crucial role of ROS for Ht-2-induced apoptosis. Collectively, our data suggest that Ht-2 can target tumor cells by inducing mitochondrion-dependent apoptosis.

Succinate accumulation induces mitochondrial reactive oxygen species generation and promotes status epilepticus in the kainic acid rat model

“…Moreover, this increase in DCF and mito-SOX was partially reversed when succinate accumulation was reduced. As an ROS marker, DCF-DA is used to assess oxidative stress [[72], [73], [74]], though there are some limitations to this technique. For example, DCF fluorescence cannot be used as a direct measure of H 2 O 2 , and is prone to multiple artifacts and artifactual amplification in ROS analysis [75].…”

Amphipathicity Determines Different Cytotoxic Mechanisms of Lysine- or Arginine-Rich Cationic Hydrophobic Peptides in Cancer Cells

“…Many existing first-line chemotherapeutics exploit the stress-induced death mechanism of cancer cells, 48 although there is often limited selectivity between cancer and noncancer cells. 49,50 Our recent study also showed that a cationic hydrophobic cyclometalated iridium complex can induce endoplasmic reticulum stress and apoptosis in cancer cells. 51 In this study, we demonstrated that 6 can induce a significantly higher level of ROS in cancer cells; thus, 6 displays a higher selectivity in killing cancer cells than normal cells.…”

“…Because of their rapid growth, frequent cell divisions, and active preparation for metastasis, cancer cells are subject to metabolically challenged conditions and are significantly reliant on ROS-response pathways, which can lead to the increased sensitivity of cancer cells to stress-inducing treatments, compared to normal cells. Many existing first-line chemotherapeutics exploit the stress-induced death mechanism of cancer cells, although there is often limited selectivity between cancer and noncancer cells. , Our recent study also showed that a cationic hydrophobic cyclometalated iridium complex can induce endoplasmic reticulum stress and apoptosis in cancer cells . In this study, we demonstrated that 6 can induce a significantly higher level of ROS in cancer cells; thus, 6 displays a higher selectivity in killing cancer cells than normal cells.…”

Tumor Microenvironment‐Triggered Aggregated Magnetic Nanoparticles for Reinforced Image‐Guided Immunogenic Chemotherapy

“…It has been reported that the internalized oxaliplatin can induce an intracellular H 2 O 2 generation, via NOXs activation and SODs‐mediated superoxide anion (O 2 ·− ) dismutation. Fortunately, H 2 O 2 also is the substrate of Fenton's reaction.…”