Caspase-independent cell death revealed in human gastric cancer cell lines, MKN45 and KATO III treated with phenoxazine derivatives.

Abstract

We examined whether phenoxazine derivatives such as 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1) and 2-aminophenoxazine-3-one (Phx-3) may have anticancer effects on the human gastric cancer cell lines, MKN45, MKN74, MKN7 and KATO III in vitro. Phx-1 inhibited the growth of these cancer cells in a dose- and time-dependent manner. The IC50 was approximately 65, 25, 100 and 70 microM for MKN45, MKN74, MKN7 and KATO III respectively, after 72 h. Phx-3 exerted stronger antiproliferative effects against these cancer cells (IC50: approximately 5, 1, 10 and 10 microM for MKN45, MKN74, MKN7 and KATO III, respectively, after 72 h) than Phx-1. Phx-1 and Phx-3 increased the population of TUNEL-positive cells in MKN45 and KATO III time-dependently from 24 to 72 h, suggesting that Phx-1 and Phx-3 have apoptotic activity against these gastric cancer cells. The activity of effector caspase-3 significantly increased in MKN45 treated with Phx-3 for 24 h, but did not altered in the cells treated with Phx-1 for 24 h. When z-VAD-fmk, a pan-caspase inhibitor, was co-treated for 24 h, Phx-3-stimulated caspase-3 activity in MKN45 was reversed to the levels of normal activity, while the antiproliferative and apoptotic effects of Phx-3 against the cells were maintained. The activity of caspase-3 was not activated in KATO III by 24 h exposure for Phx-1 or Phx-3. In conclusion, both phenoxazines prevent the growth of the human gastric cancer cell lines, MKN45 and KATO III in vitro, and cause the apoptosis of these cell lines via a caspase-independent pathway. Although the intracellular action mechanisms of Phx-1 and Phx-3 are still unclear, these phenoxazines may be useful for the treatment of gastric cancer in the future.

• Authors: Teruhiko Kasuga, Takafumi Tabuchi, Ken Shirato, Kazuhiko Imaizumi, Akio Tomoda
• Journal: Oncology reports (Oncol Rep) Vol. 17 Issue 2 Pg. 409-15 (Feb 2007) ISSN: 1021-335X [Print] Greece
• PMID: 17203181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Oxazines
• DNA
• phenoxazine
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Survival
• DNA (metabolism)
• Dose-Response Relationship, Drug
• Humans
• Inhibitory Concentration 50
• Models, Genetic
• Necrosis
• Oxazines (pharmacology)
• Stomach Neoplasms (drug therapy, pathology)
• Time Factors