Radiosensitizing Effect of 5-Aminolevulinic Acid and Protoporphyrin IX on Carbon-ion Beam Irradiation.

BACKGROUND/AIM: Carbon-ion beam is one of the most advanced radiations used for cancer treatment. However, there are tumors that are difficult to suppress with carbon-ion beam alone, thus necessitating development of drugs that can enhance its therapeutic effect. In this regard, the radiosensitizing effect of 5-aminolevulinic acid (ALA) and protoporphyrin IX (PpIX), that is a metabolic intermediate of ALA, on carbon-ion beam was investigated. MATERIALS AND METHODS: Radiosensitizing activity, mitochondrial ROS and DNA double-strand break production of ALA and PpIX were evaluated by irradiation with 1.0 or 1.5-Gy carbon-ion beam to mouse mammary EMT6 tumor cells. RESULTS: Combination of carbon-ion beam and ALA or PpIX showed a significant enhancement of its cytotoxic activity through a significant increase in ROS production in mitochondria. Furthermore, the combined activity of carbon-ion beam and ALA resulted in a significant increase in DNA double-strand breakage. CONCLUSION: ALA selectively accumulates in the mitochondria and PpIX synthesized from ALA reacts with carbon-ion beam to produce ROS that exert antitumor activity.

Design and Synthesis of Novel Anti-metastatic Hypoxic Cytotoxin TX-2137 Targeting AKT Kinase.

BACKGROUND: The hypoxic microenvironment plays a crucial role in the malignant progression of tumor cells. Moreover, AKT, a serine/threonine kinase, is activated by various extracellular growth factors and is important for cell growth, survival, and motility of leukocytes, fibroblasts, endothelial cells, and tumor cells. Therefore, we aimed to design an anti-metastatic hypoxic cytotoxin which has inhibitory effects on AKT. RESULTS: TX-2137 was designed and synthesized based on the structural similarity of a preexisting AKT1/2 kinase inhibitor and a hypoxic cytotoxin tirapazamine. TX-2137 effectively reduced the expression of phosphorylated AKT and matrix metalloproteinase 9 (MMP9) and showed strong inhibition of the proliferation of B16-F10, HT-1080, and MKN-45 cells. In addition, TX-2137 exhibited hypoxia-selective cytotoxicity towards A549 cells and inhibited liver metastasis of B16-F10 cells in a xenograft chick embryo model in the same way as doxorubicin. CONCLUSION: TX-2137 may be a potent lead compound in the development of a novel anti-metastatic AKT kinase inhibitor.