Concentration-dependent radiosensitizing effect of docetaxel in esophageal squamous cell carcinoma cells.

Abstract

Taxanes, paclitaxel and docetaxel (DTX) are anticancer agents that exhibit cytotoxicity by inhibiting microtubule polymerization. They enhance the radiosensitivity of various cancers by blocking the cell cycle in the most radiosensitive G2/M phase. Recently, taxanes have been reported to have different mechanisms of action depending on dose intensity. However, the mechanism of the radio-enhancing effect of DTX in relation to the drug dose intensity is not clearly understood. In the present study, we experimentally investigated the radio-enhancing effects of various concentrations of DTX against esophageal squamous cell cancer (ESCC); KES cells were used for in vitro confirmation of the effective administration schedule for DTX in chemoradiotherapy involving ESCC. DTX enhanced radiation cell killing in a concentration-dependent manner in KES cells. High cytotoxic concentrations (>10 nM) of DTX strongly enhanced radiosensitivity. Low concentrations (<1 nM) of DTX that did not have a cytotoxic effect showed a radio-enhancing effect by inducing DNA double strand breaks and apoptosis after irradiation. Low and high concentrations of DTX induced radiosensitive G0/G1 and G2/M phase arrest, respectively in KES cells. Cells treated with high concentrations of DTX exhibited nuclear aggregation associated with apoptotic change. In contrast, cells treated with low concentrations of DTX displayed multi-nucleation or unequal division. In conclusion, enhancement of the radiosensitivity of ESCC cells by DTX was demonstrated, even using nanomolar concentrations that did not have a cytotoxic effect. DTX has different radio-enhancing mechanisms depending on its concentration. Therefore, weekly administration of DTX might effectively enhance radiation cytotoxicity in the treatment of ESCC.

• Authors: Shohei Miyanaga, Itasu Ninomiya, Tomoya Tsukada, Koichi Okamoto, Shinichi Harada, Shinichi Nakanuma, Seisho Sakai, Isamu Makino, Jun Kinoshita, Hironori Hayashi, Keishi Nakamura, Katsunobu Oyama, Hisatoshi Nakagawara, Tomoharu Miyashita, Hidehiro Tajima, Hiroyuki Takamura, Sachio Fushida, Tetsuo Ohta
• Journal: International journal of oncology (Int J Oncol) Vol. 48 Issue 2 Pg. 517-24 (Feb 2016) ISSN: 1791-2423 [Electronic] Greece
• PMID: 26676807 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Radiation-Sensitizing Agents
• Taxoids
• Docetaxel
• Paclitaxel

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (drug therapy)
• Cell Cycle (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded (drug effects)
• Docetaxel
• Dose-Response Relationship, Drug
• Esophageal Neoplasms (drug therapy)
• Esophageal Squamous Cell Carcinoma
• Humans
• Paclitaxel (pharmacology)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (pharmacology)
• Taxoids (pharmacology)