p-terphenyl derivatives from the mushroom Thelephora aurantiotincta suppress the proliferation of human hepatocellular carcinoma cells via iron chelation.

A novel 2',3'-dihydroxy-p-terphenyl derivative, thelephantin O (TO), which has cancer-selective cytotoxicity, was isolated. This study investigated the underlying basis of the cytotoxicity of 2',3'-dihydroxy-p-terphenyl compounds in view of their ability to chelate metal ions. FeCl(2) significantly reduced TO-induced cytotoxicity, whereas several other salts of transition metals and alkaline-earth metals did not. A structure-activity relationship study using newly synthesized p-terphenyl derivatives revealed that o-dihydroxy substitution of the central benzene ring was necessary for both the cytotoxicity and Fe(2+) chelation of the compounds. Real-time PCR array and cell cycle analysis revealed that the TO-induced cytotoxicity was attributed to cell cycle arrest at the G1 phase via well-known cell cycle-mediated genes. The TO-induced changes in the cell cycle and gene expression were completely reversed by the addition of FeCl(2). Thus, it was concluded that Fe(2+) chelation occurs upstream in the pivotal pathway of 2',3'-dihydroxy-p-terphenyl-induced inhibition of cancer cell proliferation.

Cell surface marker phenotypes and gene expression profiles of murine radiation-induced acute myeloid leukemia stem cells are similar to those of common myeloid progenitors.

Radiation exposure induces acute myeloid leukemia (AML) in humans and mice. Recent studies postulated that AML stem cells of spontaneous human AML arise from hematopoietic stem cells. However, other studies support the possibility that short-lived committed progenitors transform into AML stem cells, accompanied by a particular gene mutation. It remains unclear whether AML stem cells are present in radiation-induced AML, and information regarding AML-initiating cells is lacking. In this study, we identified and analyzed AML stem cells of mice with radiation-induced AML. The AML stem cells were identified by transplanting 100 bone marrow cells from mice with radiation-induced AML. We injected 100 cells of each of seven cell populations corresponding to different stages of hematopoietic cell differentiation and compared the latencies of AMLs induced in recipient mice. The identified radiation-induced AML stem cells frequently displayed similarities in both CD antigen and gene expression profiles with normal common myeloid progenitors. The number of common myeloid progenitor-like AML stem cells was significantly increased in mice with radiation-induced AML, but the progeny of common myeloid progenitors was decreased. In addition, analysis of radiation effects on the hematopoietic system showed that common myeloid progenitor cells were extremely radiosensitive and that their numbers remained at low levels for more than 2 months after radiation exposure. Our results suggest that murine radiation-induced AML stem cells arise from radiosensitive cells at a common myeloid progenitor stage.

Enhanced transplantability of a cell line from a murine ovary granulosa cell tumour in syngeneic B6C3F(1) mice continuously irradiated with low dose-rate gamma-rays.

PURPOSE: To understand the mechanisms of life-shortening due to early neoplastic death caused by chronic low dose-rate (LDR; 20 mGy/22 h/day) radiation which accumulates to a high dose (HD; 8 Gy) (LDR/HD) as reported previously. MATERIALS AND METHODS: Female B6C3F(1) mice were continuously exposed to LDR/HD gamma-rays under specific-pathogen-free (SPF) conditions for 400 days. OV3121 cells, which were derived from an ovarian granulosa cell tumour that arose in irradiated B6C3F(1) mice, were inoculated into LDR/HD irradiated and age-matched non-irradiated control mice. The transplantability of tumour cells as well as T cell subsets and the proliferative activities of T cells were compared between irradiated and non-irradiated mice. RESULTS: We found that tumour formation of subcutaneously inoculated tumour cells occurred earlier in irradiated mice than in non-irradiated mice. Proliferative activity of draining lymph node lymphocytes against transplanted tumour cells as well as allogeneic mixed lymphocyte reactions were significantly reduced in irradiated mice compared to non-irradiated mice. CONCLUSIONS: These results suggest that decreased tumour-specific immune response due to LDR/HD irradiation may enhance tumorigenesis resulting in life-shortening of mice after chronic LDR/HD irradiation.